High voltage connectors and electrodes for pulse generators

ABSTRACT

A handheld, therapeutic electrode and connector that are compatible with high voltages from a pulse generator are disclosed. The electrode includes therapeutic terminals on a tip configured to deliver high voltage pulses safely to a patient. The electrode includes sleeves, bosses, wiring channels, and other features that maximize a minimum clearance distance (across non-conductive surfaces) and air clearance between conductive connectors themselves or the connectors and a user, thus preventing dangerous arcing. Internal surfaces and seams are taken into account. The connector and its mating outlet can include similar features to maximize clearance distance. Skirts, skirt holes, and finger stops are also employed, and they can be on either the connector or outlet, or the tip or handle of the electrode.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part (CIP) of U.S. patentapplication Ser. No. 15/269,273, filed Sep. 19, 2016, which is herebyincorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

The present application generally relates to high voltage connectors andelectrodes for applying high voltage electrical pulses to patients.Specifically, the connectors and electrodes deliver high voltageelectrical pulses received from a high voltage pulse generator topatients.

BACKGROUND

Surgical excision of a tumor can result in an infection and leave ascar. Furthermore, if there are more tumors, every cancerous tumorshould be identified and individually excised by a surgeon. This can betime consuming and expensive, not to mention uncomfortable for patients.

Cancerous tumors that are internal to a patient may be especiallydifficult to remove, let alone detect and treat. Many patients' livesare turned upside down by the discovery of cancer in their bodies,sometimes which have formed relatively large tumors before beingdetected.

A “nanosecond pulsed electric field,” sometimes abbreviated as nsPEF,includes an electric field with a sub-microsecond pulse width of between0.1 nanoseconds (ns) and 1000 nanoseconds, or as otherwise known in theart. It is sometimes referred to as sub-microsecond pulsed electricfield. NsPEFs often have high peak voltages, such as 10 kilovolts percentimeter (kV/cm), 20 kV/cm, to 500 kV/cm. Treatment of biologicalcells with nsPEF technology often uses a multitude of periodic pulses ata frequency ranging from 0.1 per second (Hz) to 10,000 Hz.

NsPEFs have been found to trigger apoptosis in cancerous tumors.Selective treatment of such tumors with nsPEFs can induce apoptosiswithin the tumor cells without substantially affecting normal cells inthe surrounding tissue due to its non-thermal nature.

An example of nsPEF applied to biological cells is shown and describedin U.S. Pat. No. 6,326,177 (to Schoenbach et al.), which is incorporatedherein by reference in its entirety for all purposes.

The use of nsPEF for the treatment of tumors is a relatively new field.There exists a need for electrodes to deliver nsPEF pulses generated bya pulse generator to patients with minimal distortion and with maximumutility and safety.

SUMMARY

Some inventive aspects include high voltage electrodes and a highvoltage connectors. The electrodes include first and second terminals,configured to contact a patient, and a cable, configured to be connectedto a pulse generator via the high voltage connector.

One inventive aspect of the present disclosure includes a high voltagetherapeutic electrode apparatus. The electrode comprises at least twoconductive terminals and a safety structure configured to provide one ormore of the following minimum clearance distances: i) a minimumclearance distance between the at least two conductive terminals, ii) aminimum clearance distance between each of the at least two conductiveterminals and a user, or iii) both minimum clearance distances.

In some embodiments, the electrode includes a tip comprising aninsulative tip housing, a plurality of therapeutic terminals supportedby the tip insulative housing, and connection terminals connected withthe therapeutic terminals. The apparatus also includes a handlecomprising an insulative handle housing, electrical connectors adaptedto mate with the connection terminals of the tip, the electricalconnectors connected to an input cable, and a sleeved receptacle. Theapparatus includes an insulative boss or other portion having a wiringchannel within, the insulative portion mating with the sleevedreceptacle. One of the sleeved receptacle and insulative portion iswithin the tip, and the other of the sleeved receptacle and insulativeportion is within the handle, the tip and handle mating together. One orboth of the insulative portion and the sleeved receptacle is sized andconfigured to provide a minimum clearance distance between theconnection terminals, the minimum clearance distance including distanceacross internal surfaces of the sleeved receptacle, insulative boss, orwiring channel.

The minimum clearance distance can be determined based at least in parton an expected voltage applied. The minimum clearance distance betweenthe connections terminals can equal or exceed 0.85 centimeters. Theapparatus can be sized and configured to provide a second minimumclearance distance between the therapeutic terminals and a hand gripportion on the handle and wherein the second minimum clearance distanceequals or exceeds 0.85 centimeters

A second minimum clearance distance between the therapeutic terminalsand a hand grip portion on the handle can equal or exceed 0.85centimeters. An insulative safety structure can be configured toincrease the second minimum clearance distance between the therapeuticterminals and the hand grip portion on the handle. The insulative safetystructure can include a boss, skirt, skirt hole, shield, finger stop, orother safety structure.

The insulative safety structure can be further configured to provide athird minimum clearance distance between the connection terminals and ahand grip portion on the handle. The third minimum clearance distancecan equal or exceed 0.85 centimeters. This insulative safety structurecan include a boss, skirt, skirt hole, shield, finger stop, or othersafety structure.

A length of the therapeutic terminals can be adjustable. The insulativetip portion can be movable relative to the therapeutic terminals inorder to adjust an exposed length of the therapeutic terminals. An airclearance distance between the therapeutic terminals can be adjustable.The therapeutic terminals can be configured to rotate. Circuitry can beconfigured to count and store a number of pulses.

One inventive aspect includes a high voltage therapeutic electrodeapparatus, the apparatus including a tip comprising an insulative tiphousing, a plurality of therapeutic terminals supported by the tipinsulative housing, and connection terminals connected with thetherapeutic terminals. The apparatus includes a handle comprising aninsulative handle housing, electrical connectors adapted to mate withthe connection terminals of the tip, the electrical connectors connectedto an input cable. The apparatus includes a sleeved receptacle and aninsulative boss or other portion having a wiring channel within, theinsulative portion mating with the sleeved receptacle. One of thesleeved receptacle and insulative portion is within the tip, and theother of the sleeved receptacle and insulative portion is within thehandle, the tip and handle mating together. One or both of theinsulative portion and the sleeved receptacle is sized and configured toa minimum clearance distance between one of the connection terminals anda hand grip portion on the handle, the minimum clearance distanceincluding distance across internal surfaces of the sleeved receptacle,insulative portion, or wiring channel.

The minimum clearance distance can be determined based at least in parton an expected voltage applied. The minimum clearance distance betweenthe connections terminals can equal or exceed 0.85 centimeters.

An insulative safety structure can be configured to provide the minimumclearance distance between the therapeutic terminals and the hand gripportion on the handle. The insulative safety structure can include aboss, skirt, skirt hole, shield, finger stop, or other safety structure.

An insulative safety structure can be configured to increase a secondminimum clearance distance between the connection terminals and a handgrip portion on the handle. This insulative safety structure can includea boss, skirt, skirt hole, shield, finger stop, or other safetystructure.

One inventive aspect includes a high voltage connector apparatusincluding an outlet having electrical terminals and a connectorconfigured to mate with the outlet, the connector having electricalterminals. The apparatus includes at least two insulative bosses orother portions, wherein the at least two insulative portions is on theoutlet or the connector, and the other of the outlet of the connectorincludes holes into which the at least two insulative portions mate. Oneor both of the insulative portion and the sleeved receptacle is sizedand configured to provide a minimum clearance distance between theelectrical terminals of the outlet or between the electrical terminalsof the connector, the minimum clearance distance including distanceacross surfaces of an insulative boss or a hole.

The minimum clearance distance can equal or exceed 0.85 centimeters.

The apparatus can further include a skirt and a skirt hole configured tomate with the skirt, wherein the skirt is on the outlet or theconnector, and the skirt hole is on the other of the outlet orconnector, the skirt providing the minimum clearance distance betweenthe electrical terminals of the outlet or between the electricalterminals of the connector.

The apparatus can further include multiple skirts and mating skirtholes. The skirt can surround the at least two insulative bosses orholes. Or, the skirt can surround a single insulative boss or a singlehole. The apparatus can further include circuitry configured to countand store a number of pulses through the connector. The minimumclearance distance can be determined based at least in part on anexpected voltage applied to the electrical terminals.

One inventive aspect includes a swappable or fixed, non-swappable tipapparatus for a high voltage nanosecond pulsed electric field (nsPEF)therapeutic electrode. The apparatus includes an insulative housing fora tip, the insulative housing having a sleeved receptacle, at least twotip wiring channels sealed from one another within the housing, at leasttwo insulative bosses or other portions that project from a bottom ofthe sleeved receptacle toward an opening of the sleeved receptacle, aninside of each insulative portion forming a portion of one of the tipwiring channels, a pair of high voltage input terminals, each terminallocated atop one of the respective insulative portions, a set oftherapeutic needle electrodes extending from the insulative housing, andinternal electrical wires, each internal electrical wire segregated inone of the tip wiring channels and connecting at least one of thetherapeutic needle electrodes to one of the input terminals.

A minimum clearance distance between the high voltage terminals, forexample, may be equal to or exceed 0.85 centimeters, the minimumclearance distance including distance across a surface of the sleevedreceptacle, one of the at least two insulative bosses, or one of the atleast two tip wiring channels. The apparatus can include a handle havinginsulative terminal channels and conductive connectors therein, eachinsulative terminal channel adapted to slidably enclose a respectiveinput pulse channel and boss when a conductive connector is mated withan input pulse terminal. The apparatus can include a hand guardsurrounding the tip at a fixed distance from the therapeutic needleelectrodes.

The apparatus can include a tab and latch notch projecting from theinsulative housing, the latch notch configured to resiliently mate witha latch hook. At least one fiducial can project from the insulativehousing and radially aligned with a central point of the set oftherapeutic needle electrodes. The at least one fiducial can include asymmetric set of fiducials around the central point of the set oftherapeutic needle electrodes.

One inventive aspect includes a tip apparatus for a high voltagenanosecond pulsed electric field (nsPEF) therapeutic electrode. Theapparatus includes an insulative housing for a tip, the insulativehousing having a sleeved receptacle, at least two tip wiring channelssealed from one another within the housing, at least two insulativebosses or other portions that project from a bottom of the sleevedreceptacle toward an opening of the sleeved receptacle, an inside ofeach insulative portion forming a portion of one of the tip wiringchannels, a pair of high voltage input terminals, each terminal locatedatop one of the respective insulative portions, and a set of therapeuticneedle electrodes extending from the insulative housing. One or both ofthe insulative portion and the sleeved receptacle is sized andconfigured to provide a minimum clearance distance between the highvoltage terminals, the minimum clearance distance including distanceacross surfaces of the insulative portions or tip wiring channels.

One inventive aspect is an electrode electrically connectable to a pulsegenerator. The electrode is configured to deliver a pulse generated bythe pulse generator to a patient, and includes a plurality oftherapeutic terminals configured to deliver the pulse to the patient,first and second electrical pulse inlet holes, and a first pulse inputterminal, where the first pulse input terminal is in the firstelectrical pulse inlet hole and is spaced apart from an entrance to thefirst electrical pulse inlet hole by a distance greater than about 2.5cm, and the first pulse input terminal is electrically connected withone or more of the therapeutic terminals. The electrode also includes asecond pulse input terminal, where the second pulse input terminal is inthe second electrical pulse inlet hole and is spaced apart from anentrance to the second electrical pulse inlet hole by a distance greaterthan about 2.5 cm, and where the second pulse input terminal iselectrically connected with one or more of the therapeutic terminals.

The electrode can include a guard configured to maintain a user's hand aminimum clearance distance away from the therapeutic terminals. It canfurther include a cable, the cable being electrically connected with thefirst connection terminal by a first wire extending from the cable andthe cable being electrically connected with the second connectionterminal by a second wire extending from the cable, wherein the cable isconnectable to a pulse generator. The first wire may not insulated, anda first portion of the second wire is routed from the cable away fromthe second connection terminal, and a second portion of the second wireis routed from the first portion toward the second connection terminal.

The electrode can include a resistor electrically connected to the firstand second pulse input terminals. The resistor can have a valuecorresponding with an attribute of the electrode. The electrode canfurther include a resistor electrically connected to one of the firstand second pulse input terminals, the electrode being configured toconduct current to or from the one of the therapeutic terminals throughthe resistor. The electrode can include a plurality of fiducialsradially aligned with a geometric center of the therapeutic terminals.

Another inventive aspect is an electrode electrically connectable to apulse generator. The electrode is configured to deliver a pulsegenerated by the pulse generator to a patient, and the electrodeincludes a plurality of therapeutic terminals configured to deliver thepulse to the patient. The electrode also includes a handle including askirt, and first and second connection terminals within the skirt, and atip, connected to the handle. The tip includes first and secondconnectors, configured to mechanically and electrically connect with theconnection terminals of the handle while the tip is connected to thehandle, and a skirt hole, configured to receive the skirt of the handlewhile the tip is connected to the handle. The skirt includes first andsecond holes configured to receive the first and second connectors ofthe tip while the tip is connected to the handle, and the first andsecond holes of the skirt are respectively separated from the first andsecond connection terminals by a distance greater than about 2.5 cmwhile the tip is connected to the handle.

The tip can be removably connected to the handle. It can be removablyconnected to the handle by a latch comprising a latch hook and a latchnotch. The tip can include a guard configured to maintain a user's handa minimum clearance distance away from the therapeutic terminals.

The electrode can further include a cable, the cable being electricallyconnected with the first connection terminal by a first wire extendingfrom the cable, the cable being electrically connected with the secondconnection terminal by a second wire extending from the cable, whereinthe cable is connectable to a pulse generator. The first wire may notinsulated, and a first portion of the second wire may be routed from thecable away from the second connection terminal, and a second portion ofthe second wire may be routed from the first portion toward the secondconnection terminal. The handle can include first and second bosses,wherein the first wire extends from the cable to the first connectionterminal through the first boss, wherein the second wire extends fromthe cable to the second connection terminal through the second boss,wherein the first boss includes a first slot extending along a side ofthe first boss, and wherein the second boss includes a second slotextending along a side of the second boss.

The electrode can include a resistor electrically connected to the firstand second connection terminals by first and second conductors. Theresistor can have a value corresponding with an attribute of theelectrode. The resistor can be electrically connected to one of thefirst and second connection terminals, wherein the electrode isconfigured to conduct current to or from the one of the therapeuticterminals through the resistor.

The electrode can further include a plurality of fiducials radiallyaligned with a geometric center of the therapeutic terminals. Thedistance between first and second connection terminals along any path onany surface or combination of surfaces can be greater than 2.5 cm.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a nanosecond pulse generator apparatus in accordancewith an embodiment.

FIG. 2 illustrates a pulse profile for both voltage and current inaccordance with an embodiment.

FIG. 3 illustrates a perspective view of a seven-needle electrode inaccordance with an embodiment.

FIG. 4 illustrates a perspective view of a two-pole electrode inaccordance with an embodiment.

FIG. 5 is an electrical schematic of a pulse generator in accordancewith an embodiment.

FIG. 6A is a schematic illustrating the pulse generator shown in FIG. 5during charge mode.

FIG. 6B is a schematic illustrating the pulse generator shown in FIG. 5during discharge mode.

FIG. 7 is an electrical schematic of an assembly of pulse generatorcircuits.

FIG. 8 is an electrical schematic of one of the pulse generator circuitsshown in FIG. 7.

FIG. 9 is an electrical schematic of one of the pulse generator stagesshown in FIG. 8.

FIG. 10 is an electrical schematic of one of the switch drivers shown inFIG. 9.

FIG. 11 is an electrical schematic of an alternative switch element.

FIG. 12 is a waveform diagram illustrating the operation of atransformer and a control voltage to a MOSFET gate.

FIG. 13 is an alternative electrical schematic of a pulse generatorshown in FIG. 1.

FIG. 14 is an alternative electrical schematic of a pulse generatorshown in FIG. 1.

FIG. 15 is a block diagram of a nsPEF treatment system.

FIG. 16 is a schematic illustration of an alternative pulse generator.

FIG. 17 is a schematic illustration of an electrode which may be used inthe nsPEF treatment system of FIG. 15.

FIG. 18 is a flowchart illustration of methods of using an nsPEFtreatment system.

FIG. 19 is a flowchart illustration of methods of using an nsPEFtreatment system.

FIG. 20 is a flowchart illustration of methods of using an nsPEFtreatment system.

FIG. 21 is a flowchart illustration of methods of using an nsPEFtreatment system.

FIG. 22 is an illustration of an electrode which may be used in thensPEF treatment systems discussed herein.

FIG. 23 is an illustration of an electrode which may be used in thensPEF treatment systems discussed herein.

FIG. 24 is an illustration of an electrode which may be used in thensPEF treatment systems discussed herein.

FIG. 25 is an illustration of an electrode which may be used in thensPEF treatment systems discussed herein.

FIG. 26 is an illustration of an instrument which may be used in thensPEF treatment systems discussed herein.

FIG. 27A is an illustration of a connector configured to be mated with ahousing cutaway portion.

FIG. 27B is an illustration of a connector configured to be mated with ahousing cutaway portion.

FIG. 28A is an illustration of a cross-sectional view of a connector anda housing cutaway portion.

FIG. 28B is an illustration of a cross-sectional view of a connector anda housing cutaway portion.

FIG. 28C is an illustration of a cross-sectional view of a connector anda housing cutaway portion.

FIG. 28D is an illustration of a cross-sectional view of a connector anda housing cutaway portion with a minimum clearance distance shown.

FIG. 29 is an illustration of a connector configured to be mated with ahousing cutaway portion.

FIG. 30A is an illustration of a cross-sectional view of a connector anda housing cutaway portion.

FIG. 30B is an illustration of a cross-sectional view of a connector anda housing cutaway portion.

FIG. 31A illustrate an embodiment of an electrode.

FIG. 31B illustrate an embodiment of an electrode.

FIG. 32A illustrates an embodiment of a handle.

FIG. 32B illustrates an embodiment of a handle.

FIG. 32C illustrates an embodiment of a handle.

FIG. 33A illustrates an embodiment of a handle cap.

FIG. 33B illustrates an embodiment of a handle cap.

FIG. 34A illustrates an embodiment of a handle base.

FIG. 34B illustrates an embodiment of a handle base.

FIG. 35A illustrates an embodiment of a tip.

FIG. 35B illustrates an embodiment of a tip.

FIG. 36 illustrates an embodiment of a tip base.

FIG. 37 illustrates an embodiment of a tip cap.

FIG. 38 illustrates an embodiment of a tip cap.

FIG. 39 illustrates an embodiment of a tip cap.

FIG. 40 illustrates an embodiment of a tip cap.

FIG. 41 illustrates an embodiment of a tip cap.

FIG. 42A illustrates an embodiment of an electrode.

FIG. 42B illustrates an embodiment of an electrode.

FIG. 42C illustrates an embodiment of an electrode with a minimumclearance distance shown.

FIG. 43A illustrates an embodiment of an electrode.

FIG. 43B illustrates an embodiment of an electrode with a minimumclearance distance shown.

FIG. 44A illustrates an embodiment of a handle.

FIG. 44B illustrates an embodiment of a handle.

FIG. 45 illustrates an embodiment of a handle.

FIG. 46 illustrates an embodiment of a connector.

DETAILED DESCRIPTION

It has been shown that nanosecond pulsed electric field (nsPEF)treatments can be used to cause cancerous tumor cells to undergoapoptosis, a programmed cell death. Tests have shown that tumors canshrink to nonexistence after treatment. No drugs may be necessary. Ithas also been shown that the subject's immune system may be stimulatedto attack all similar tumor cells, including those of tumors that arenot within the nsPEF-treated tumor.

A “tumor” includes any neoplasm or abnormal, unwanted growth of tissueon or within a subject, or as otherwise known in the art. A tumor caninclude a collection of one or more cells exhibiting abnormal growth.There are many types of tumors. A malignant tumor is cancerous, apre-malignant tumor is precancerous, and a benign tumor is noncancerous.Examples of tumors include a benign prostatic hyperplasia (BPH), uterinefibroid, pancreatic carcinoma, liver carcinoma, kidney carcinoma, coloncarcinoma, pre-basal cell carcinoma, and tissue associated withBarrett's esophagus.

A “disease” includes any abnormal condition in or on a subject that isassociated with abnormal, uncontrolled growths of tissue, includingthose that are cancerous, precancerous, and benign, or other diseases asknown in the art.

“Apoptosis” of a tumor or cell includes an orderly, programmed celldeath, or as otherwise known in the art.

“Immunogenic apoptosis” of a tumor or cell includes a programmed celldeath that is followed by an immune system response, or as otherwiseknown in the art. The immune system response is thought to be engagedwhen the apoptotic cells express calreticulin or another antigen ontheir surfaces, which stimulates dendritic cells to engulf, consume, orotherwise commit phagocytosis of the targeted cells leading to theconsequent activation of a specific T cell response against the targettumor or cell.

Pulse lengths of between 10 and 900 nanoseconds for nsPEF have beenparticularly studied to be effective in stimulating an immune response.Pulse lengths of about 100 nanoseconds are of particular interest inthat they are long enough to carry sufficient energy to be effective atlow pulse numbers but short enough to be effective in the mannerdesired.

A time of “about” a certain number of nanoseconds includes times withina tolerance of ±1%, 2%, 3%, 4%, 5%, 7.5%, 10%, 15%, 20%, 25% or otherpercentages, or fixed tolerances, such as ±0.1, ±0.2, ±0.3, ±0.4, ±0.5,±0.7, ±1.0, ±2.0, ±3.0, ±4.0 ±5.0, ±7.0, ±10, ±15, ±20, ±25, ±30, ±40,±50, ±75 ns, or other tolerances as acceptable in the art in conformancewith the effectivity of the time period.

Immune system biomarkers can be measured before and/or after nsPEFtreatment in order to confirm that the immune response has beentriggered in a patient. Further, nsPEF treatment can be paired with aCD47-blocking antibody treatment to better train CD8+T cells (i.e.,cytotoxic T cells) for attacking the cancer.

FIG. 1 illustrates a nanosecond pulse generator system in accordancewith an embodiment. NsPEF system 100 includes electrode 102, footswitch103, and interface 104. Footswitch 103 is connected to housing 105 andthe electronic components therein through connector 106. Electrode 102is connected to housing 105 and the electronic components thereinthrough high voltage connector 112. NsPEF system 100 also includes ahandle 110 and storage drawer 108. As shown in DETAIL A portion of FIG.1, nsPEF system 100 also includes holster 116, which is configured tohold electrode 102 at its handle portion 114.

A human operator inputs a number of pulses, amplitude, pulse duration,and frequency information, for example, into a numeric keypad or a touchscreen of interface 104. In some embodiments, the pulse width can bevaried. A microcontroller sends signals to pulse control elements withinnsPEF system 100. In some embodiments, fiber optic cables allow controlsignaling while also electrically isolating the contents of the metalcabinet with nsPEF generation system 100, the high voltage circuit, fromthe outside. In order to further isolate the system, system 100 may bebattery powered instead of from a wall outlet.

FIG. 2 illustrates a pulse profile for both voltage and current inaccordance with an embodiment. Output from the nsPEF system 100 withvoltage on the top of the figure and current on the bottom for a firstand second pulses. The first pulse has an amplitude of about 15 kV, acurrent of about 50 A, and a duration of about 15 ns. The second pulsehas an amplitude of about 15 kV, a current of about 50 A, and a durationof about 30 ns. Thus, 15 kV may be applied to suction electrodes having4 mm between the plates so that the tumors experience 47.5 kV/cm, andcurrent between 12 and 50 A. Given a voltage, current depends heavily onthe electrode type and tissue resistance.

While FIG. 2 illustrates a specific example, other pulse profiles mayalso be generated. For example, in some embodiments, rise and/or falltimes for pulses may be less than 20 ns, about 20 ns, about 25 ns, about30 ns, about 40 ns, about 50 ns, about 60 ns, about 75 ns, or greaterthan 75 ns. In some embodiments, the pulse voltage may be less than 5kV, about 5 kV, about 10 kV, about 15 kV, about 20 kV, about 25 kV,about 30 kV, or greater than 30 kV. In some embodiments, the current maybe less than 10 A, about 10 A, about 25 A, about 40 A, about 50 A, about60 A, about 75 A, about 100 A, about 125 A, about 150 A, about 175 A,about 200 A, or more than 200 A. In some embodiments, the pulse durationmay be less than 10 ns, about 10 ns, about 15 ns, about 20 ns, about 25ns, about 30 ns, about 40 ns, about 50 ns, about 60 ns, about 75 ns,about 100 ns, about 125 ns, about 150 ns, about 175 ns, about 200 ns,about 300 ns, about 400 ns, about 500 ns, about 750 ns, about 1 μs,about 2 μs, about 3 μs, about 4 μs, about 5 μs, or greater than 5 μs.

FIG. 3 illustrates a perspective view of a seven-needle suctionelectrode 300 in accordance with an embodiment. In electrode 300, sheath301 surrounds seven sharp terminals 302 with an broad opening at adistal end. When the open end is placed against a tumor, air isevacuated from the resulting chamber through vacuum holes 304 to drawthe entire tumor or a portion thereof into the chamber. The tumor isdrawn so that one or more of the terminals 302 preferably penetrates thetumor. Sharp ends of the terminals 302 are configured to pierce thetumor. The center terminal 302 may be at one polarity, and the outer sixterminals 302 may be at the opposite polarity. Nanopulses electricfields can then be precisely applied to the tumor using nsPEF system 100(see FIG. 1).

The terminals 302 can be apposed, one of each positive and negative pairof terminals 302 on one side of a tumor and the other electrode of thepair on an opposing side of the tumor. Opposing sides of a tumor caninclude areas outside or within a tumor, such as if a needle terminal302 pierces a portion of the tumor.

FIG. 4 illustrates a two-pole suction electrode 400 in accordance withan embodiment. In electrode device 400, sheath 401 surrounds two broadterminals 402 on opposite sides of a chamber. When air is evacuatedthrough vacuum holes 404 and a tumor is pulled within the chamber, theopposing terminals 402 apply nsPEF pulses to the tumor.

The nature of the electrode used mainly depends upon the shape of thetumor. Its physical size and stiffness can also be taken into account inselection of a particular electrode type.

U.S. Pat. No. 8,688,227 B2 (to Nuccitelli et al.) discloses othersuction electrode-based medical instruments and systems for therapeuticelectrotherapy, and it is hereby incorporated by reference.

If there are multiple tumors in a subject, a surgeon can select a singletumor to treat based on the tumor's compatibility with electrodes. Forexample, a tumor that is adjacent to a stomach wall may be more easilyaccessible than one adjacent a spine or the brain. Because a nsPEF pulseis preferably applied so that the electric field transits through asmuch tumor mass as possible while minimizing the mass of non-tumor cellsthat are affected, a clear path to two opposed ‘poles’ of a tumor mayalso be a selection criterion.

For tumors on or just underneath the skin of subject, needle terminalscan be used percutaneously. For locations deeper within a subject, aretractable terminal can fit into a gastroscope, bronchoscope,colonoscope, or other endoscope or laparoscope. For example, a tumor ina patient's colon can be accessed and treated using a terminal within acolonoscope.

Barrett's esophagus, in which portions of tissue lining a patient'sesophagus are damaged, may be treated using an electrode placed on aninflatable balloon.

Embodiments of nanosecond pulsed power generators produce electricpulses in the range of single nanoseconds to single microseconds. Thepulses are created by rapid release of energy stored in, for example, acapacitive or inductive energy reservoir to a load in a period that isgenerally much shorter than the charging time of the energy reservoir.

Conventional capacitive-type pulsed generators include pulse formingnetworks, which provide fixed pulse duration and impedance. With priorknowledge of a load's resistance, a pulse forming network with impedancethat matches the load can be used. But for broader applications,especially when the load resistance is unknown, it is desirable to havea pulse generator with a flexibility of impedance matching and variationof pulse duration. Such flexibility can be implemented by switching acapacitor with a controllable switch. In this case, the capacitor can beregarded as a “voltage source” and can adapt to various load resistance.The switched pulse amplitude can then have the same voltage as thevoltage of the capacitor. The pulse width is accordingly determined bythe switch “on” time.

The selection of switches in nanosecond pulse generators is limitedbecause of the high voltages, high currents, and fast switching timesinvolved.

Spark gap switches, typically used in pulsed power technology, arecapable of switching high voltages and conducting high currents. Butthey can only be turned on, and stopping the current flow in the middleof conduction is impossible. Besides spark gaps, other types of highvoltage, high power switches are available, such as: magnetic switches,vacuum switches (Thyratrons for example), and certain high-voltagesemiconductor switches.

Magnetic switches, relying on the saturation of magnetic core, changefrom high impedance to low impedance in the circuit. They can be turnedon above a certain current threshold but will not be turned off untilall the current is depleted by the load.

Vacuum switches are a good option for high voltage and high repletionrate operation, but similar to magnetic switches, they also can be onlyturned on, but cannot be turned off at a predetermined time.

Some types of high-voltage semi-conductor switches may also beconsidered. Thyristors and insulated gate bipolar transistors (IGBTs)may, in some embodiments be used. However, the turn-on times ofThyristors and IGBTs limit their usefulness.

Metal-oxide-semiconductor field-effect transistors (MOSFETs) haveinsufficient maximum drain to source voltage ratings (e.g. <1 kV) andinsufficient maximum drain to source current ratings (e.g. <50 A) to beused in conventional pulse generator architectures to produce thevoltage and current necessary for the applications discussed herein. Ifthey were used, a large number of stages would be needed in order toproduce high-amplitude output voltages. However, in conventional Marxgenerator architectures with a large number of stages, the Marxgenerator goes into an underdamped mode instead of a critically dampedmode, resulting in loss in overshoot. As a result, the overall voltageefficiency decreases. For example, a voltage efficiency of a Marxgenerator may be 80% at 5 stages but decrease to 50% at 20 stages.

Furthermore, as the number of stages is increased, the impedance of theMarx generator also increases. This reduces the total energy deliverableto the load. This is particularly unfavorable for driving low impedanceloads and long pulses.

In addition, the charging losses in the charging resistors alsoincreases with the increased number of stages. As a result, such Marxgenerators are unsuitable for high repetition rate operation.

Therefore, in order to produce high voltage pulses, simply increasingthe number of stages will cause a series of problems, including lowefficiency, high impedance, etc. Because there is a tradeoff between thenumber of the stages and the actual output voltage, using conventionalMarx generators cannot produce high voltage pulses which are sufficientfor the applications discussed herein.

Some embodiments of this disclosure include a tunable, high voltage,nanosecond pulse generator. The switches may be power MOSFETs, whichmay, for example, be rated for a voltage of 1 kV and current of up to 30A. Voltage is scaled up by a Marx-switch stack hybrid circuit. In eachMarx generator stage, a particularly configured stack of MOSFETs isused. As a result, the charging voltage for each stage is greater thanthe rated maximum for a single switch.

A technical advantage of the configuration is that the overall outputvoltage can be increased with just a few stages (e.g. <=5). As a result,the problems discussed above with Marx generators having a large numberof stages are avoided and high efficiency, low impedance, and largevariability in the pulse duration can be achieved.

Such an architecture also allows much easier control as only one triggercircuit may be needed for each stage. One additional benefit is that thepulse generator has low impedance, so it will be able to drive variousloads with high current and extended pulse duration. The scaling up ofthe current is implemented by combining multiple Marx-switch stackcircuits in parallel. The pulse duration is controlled by the closingand opening of the switch stack switches.

FIG. 5 illustrates a pulse generator circuit 500 which may be usedinside nsPEF system 100 of FIG. 1. Pulse generator circuit 500illustrates a panel comprising a Marx generator switched by three switchstacks. The nsPEF system can have a single pulse generator circuitpanel. In some embodiments, a nsPEF system includes multiple panels inparallel.

Circuit 500 includes three stages—510, 520, and 530. In someembodiments, another number of stages is used. For example, in someembodiments, 2, 4, 5, 6, 7, 8, 9, or 10 stages are used. Stage 510includes resistors 512 and 514, capacitor 515, and switch stack 516.Likewise, stage 520 includes resistors 522 and 524, capacitor 525, andswitch stack 526, and stage 530 includes resistors 532 and 534,capacitor 535, and switch stack 536. Each of these elements havestructure and functionality which is similar to the correspondingelements of stage 510.

Stage 510 has first and second input voltage input terminals 511 and 513and first and second voltage output terminals 517 and 518. Stage 520 hasfirst and second input voltage input terminals 521 and 523, and firstand second voltage output terminals 527 and 528. Stage 530 has first andsecond input voltage input terminals 531 and 533, and first and secondvoltage output terminals 537 and 538.

The first and second voltage input terminals 511 and 513 of stage 510are respectively connected to first and second power supply inputterminals V1 and V2. The first and second voltage output terminals 517and 518 of stage 510 are respectively connected to the first and secondvoltage input terminals 521 and 523 of stage 520. The first and secondvoltage output terminals 527 and 528 of stage 520 are respectivelyconnected to the first and second voltage input terminals 531 and 533 ofstage 530. The second voltage output terminal 538 of stage 530 andsecond voltage input terminal 513 of stage 510 are respectivelyconnected to first and second power output terminals VO1 and VO2.

Pulse generator circuit 500 operates in a charge mode, and in adischarge mode. During the charge mode, described below with referenceto FIG. 6A in more detail, capacitors 515, 525, and 535 are charged bycurrent received from the first and second power supply input terminalsV1 and V2. During the discharge mode, described below with reference toFIG. 6B in more detail, capacitors 515, 525, and 535 are discharged toprovide a current to a load (not shown) connected across first andsecond power output terminals VO1 and VO2.

FIG. 6A illustrates pulse generator circuit 500 during charge mode.First and second input voltages are respectively applied to first andsecond power supply input terminals V1 and V2 while each of switchstacks 516, 526, and 536 are nonconductive or open, and while first andsecond power output terminals may be disconnected from the load (notshown). Because each of switch stacks 516, 526, and 536 are open,substantially no current flows therethrough, and they are represented asopen circuits in FIG. 6A. During the charge mode, each of capacitors515, 525, and 535 are charged by current flowing through resistors 512,522, 532, 534, 524, and 514 to or toward a voltage equal to thedifference between the first and second input voltages.

Each of the switches of switch stacks 516, 526, and 536 has a breakdownvoltage rating which should not be exceeded. However, because theswitches are serially connected, the capacitors 515, 525, and 535 may becharged to a voltage significantly greater than the breakdown voltage ofthe individual switches. For example, the breakdown voltage of theswitches may be 1 kV, and the capacitors 515, 525, and 535 may becharged to a voltage of 5 kV, when 5 or more switches are used in eachswitch stack.

For example, the first and second input voltages may respectively be 5kV and 0V. In such an example, each of the capacitors 515, 525, and 535is charged to or toward a voltage equal to 5 kV. In some embodiments,the difference between the first and second input voltages is limited tobe less than 10 kV.

FIG. 6B illustrates pulse generator circuit 500 during discharge mode.First power supply input terminal V1 may be disconnected from the firstinput voltage. In some embodiments, first power supply input terminal V1remains connected to the first input voltage. Second power supply inputterminal V2 remains connected to the second input voltage. In addition,each of switch stacks 516, 526, and 536 are conductive or closed.Because each of switch stacks 516, 526, and 536 are closed, currentflows therethrough, and they are represented as conductive wires in FIG.6B. As a result, a low impedance electrical path from power supply inputterminal V2 to power output terminal VO1 is formed by switch stack 516,capacitor 515, switch stack 526, capacitor 525, switch stack 536, andcapacitor 535. Consequently, the difference between the voltages at thepower output terminals VO1 and VO2 is equal to the number of stages (inthis example, 3) times the difference between the first and second inputvoltages.

Where the first and second input voltages are respectively 5 kV and 0V,a voltage difference of 15 kV is developed across the power outputterminals VO1 and VO2.

FIG. 7 illustrates an alternative pulse generator circuit 700 which maybe used inside nsPEF system 100 of FIG. 1. This pulse generator includespanels in parallel. The number of panels can be adjusted to allow thesystem to generate different amounts of current and power.

Pulse generator circuit 700 receives input pulses across input port Vin,and generates output pulses across output port Vout in response to thereceived input pulses.

Pulse generator circuit 700 includes multiple panels or pulse generatorcircuits 710, 720, 730, and 740. Pulse generator circuit 700 alsoincludes driver 750. In this embodiment, four pulse generator circuitsare used. An alternative embodiments, fewer or more pulse generatorcircuits are used. For example, in some embodiments, 2, 3, 5, 6, 7, 8,9, 10 or another number of pulse generator circuits are used.

Each of the pulse generator circuits 710, 720, 730, and 740 may havecharacteristics similar to other pulse generator circuits discussedherein. For example, each the pulse generator circuits 710, 720, 730,and 740 may have characteristics similar to pulse generator circuit 500discussed above with reference to FIGS. 5, 6A, and 6B.

Each of pulse generator circuits 710, 720, 730, and 740 has positive andnegative DC input terminals, positive and negative control inputterminals, and positive and negative output terminals, and is configuredto generate output voltage pulses across the positive and negativeoutput terminals in response to driving signal pulses applied across thepositive and negative control input terminals. The output voltage pulsesare also based on power voltages received across positive and negativeDC power input terminals.

The driving signal pulses are generated across conductors 756 and 758 bydriver 750, which includes amplifier circuit 751, capacitor 752, andtransformer 753. In some embodiments, driver 750 also includes clampcircuits 754.

Driver 750 receives an input signal pulse at input port Vin andgenerates a driving signal pulse across conductors 756 and 758 inresponse to the input signal pulse. Amplifier circuit 751 receives theinput signal pulse and drives transformer 753 through capacitor 752,which blocks low frequency and DC signals. In response to being drivenby amplifier circuit 751, transformer 753 generates an output voltagepulse across conductors 756 and 758, such that the duration of theoutput voltage pulse is equal to or substantially equal (e.g. within 10%or 1%) to the duration of the input signal pulse at input port Vin.

In some embodiments, clamp circuits 754 are included at least to dampenpotential signals, which may otherwise be caused by resonance. Clampcircuits 754 include parallel diodes, which provide a short-circuit pathfor any current reversal, and also clamp the maximum voltage across thecomponents connected to the clamp circuits 754.

In some embodiments, transformer 753 has a 1:1 turns ratio. Inalternative embodiments, a different turns ratio is used.

Each of pulse generator circuits 710, 720, 730, and 740 receives thevoltage pulses from driver 750 across the positive and negative controlinput terminals and generates corresponding voltage pulses across thepositive and negative output terminals in response to the receivedvoltage pulses from driver 750. The voltage pulses generated across thepositive and negative output terminals have durations which are equal toor substantially equal (e.g. within 10% or 1%) to the durations of thevoltage pulses received from driver 750.

In this embodiment, the negative output terminals of pulse generatorcircuits 710, 720, 730, and 740 are directly connected to the negativeVout terminal of the output port Vout of pulse generator circuit 700. Inaddition, in this embodiment, the positive output terminals of pulsegenerator circuits 710, 720, 730, and 740 are respectively connected tothe positive Vout terminal of the output port Vout of pulse generatorcircuit 700 through diodes 715, 725, 735, and 745. Diodes 715, 725, 735,and 745 decouple pulse generator circuits 710, 720, 730, and 740 fromone another. As a consequence, interference and the associated pulsedistortion that would otherwise occur is substantially eliminated. Forexample, diodes 715, 725, 735, and 745 prevent current from one of pulsegenerator circuits 710, 720, 730, and 740 to another of pulse generatorcircuits 710, 720, 730, and 740 if the switching is not perfectlysynchronous. Diodes 715, 725, 735, and 745 also prevent current fromflowing from the pulse generator circuits 710, 720, 730, and 740 whilethey are charging.

In this embodiment, diodes 715, 725, 735, and 745 each include a singlediode. In alternative embodiments, diodes 715, 725, 735, and 745 eachinclude multiple diodes connected serially based at least upon voltageratings of the serially connected diodes. Additionally or alternatively,in some embodiments, diodes 715, 725, 735, and 745 each include multiplediodes connected in parallel based at least upon the current ratings ofthe parallel connected diodes.

In this embodiment, diodes 715, 725, 735, and 745 are connected so as toconduct current from the positive terminal of output port Vout towardpulse generator circuits 710, 720, 730, and 740, as pulse generatorcircuits 710, 720, 730, and 740 in this embodiment are configured togenerate negative pulses. In alternative embodiments, where pulsegenerator circuits are configured to generate positive pulses, diodesmay be similarly connected so as to conduct current from the pulsegenerator circuits to the positive terminal of the output port.

FIG. 8 illustrates a pulse generator circuit 800 which may be used forpulse generator circuits 710, 720, 730, and 740 of pulse generatorcircuit 1000 of FIG. 7.

Pulse generator circuit 800 receives input pulses across input port Vin,and generates output pulses across output port Vout in response to thereceived input pulses.

Pulse generator circuit 800 includes multiple pulse generator stages810, 820, and 830. In this embodiment, pulse generator circuit 700 alsoincludes driver 850, and optional common mode chokes 815, 825, and 835.

Each of the pulse generator stages 810, 820, and 830 may havecharacteristics similar to other pulse generator stages discussedherein. For example, each the pulse generator stages 810, 820, and 830may have characteristics similar to stages 510, 520, and 530 of pulsegenerator circuit 500 discussed above with reference to FIGS. 5, 6A, and6B. In some embodiments, fewer or more pulse generator stages may beused.

Each of pulse generator stages 810, 820, and 830 has positive andnegative trigger input terminals, power positive and negative DC inputterminals, and positive and negative Vo output terminals, and isconfigured to generate output voltage pulses across the positive andnegative Vo output terminals in response to driving signal pulsesapplied across the positive and negative trigger input terminals. Theoutput voltage pulses are also based on power voltages V1 and V2respectively received at power positive and negative DC input terminals.

In this embodiment, the negative Vi input terminal of pulse generatorstage 830 is connected with the negative terminal of the output portVout of pulse generator circuit 800. In addition, in this embodiment,the negative Vo output terminal of pulse generator stage 810 isconnected with the positive terminal of the output port Vout of pulsegenerator circuit 800.

In addition, as shown, the positive Vo output terminal of pulsegenerator 830 is connected with the positive Vi input terminal of pulsegenerator 820, and the negative Vo output terminal of pulse generator830 is connected with the negative Vi input terminal of pulse generator820. Furthermore, the positive Vo output terminal of pulse generator 820is connected with the positive Vi input terminal of pulse generator 810,and the negative Vo output terminal of pulse generator 820 is connectedwith the negative Vi input terminal of pulse generator 810.

The driving signal pulses for pulse generator stages 810, 820, and 830are generated across conductors 856 and 858 by driver 850, whichincludes amplifier circuit 851, capacitor 852, and transformer 853. Insome embodiments, driver 850 also includes clamp circuits 854.

Driver 850 receives an input signal pulse at input port Vin, which isconnected to conductors 756 and 758, as shown in FIG. 7 discussed above.Driver 850 generates a driving signal pulse across conductors 856 and858 in response to the input signal pulse. Amplifier circuit 851receives the input signal pulse, and drives transformer 853 throughcapacitor 852, which reduces or blocks low frequency and DC signals. Inresponse to being driven by amplifier circuit 851, transformer 853generates an output voltage pulse across conductors 756 and 758, suchthat the duration of the output voltage pulse is equal to orsubstantially equal (e.g. within 10% or 1%) to the duration of the inputsignal pulse at input port Vin.

In some embodiments, clamp circuits 854 are included at least to dampenpotential signals, which may otherwise be caused by resonance. Clampcircuits 854 include parallel diodes, which provide a short-circuit pathfor any current reversal, and also clamp the maximum voltage across thecomponents connected to the clamp circuits 854.

In some embodiments, transformer 853 has a 1:1 turns ratio. Inalternative embodiments, a different turns ratio is used.

Each of pulse generator stages 810, 820, and 830 receives the voltagepulses from driver 850 through a corresponding choke 815, 825, or 835,which blocks high frequency signals, for example, from coupling from thehigh voltage pulse generator stages 810, 820, and 830. The voltagepulses are received at the positive and negative trigger input terminalsand the pulse generator stages 810, 820, and 830 each generatecorresponding voltage pulses across the positive and negative Vo outputterminals in response to the received voltage pulses from driver 850.The voltage pulses generated across the positive and negative Vo outputterminals have durations which are equal to or substantially equal (e.g.within 10% or 1%) to the durations of the voltage pulses received fromdriver 850.

FIG. 9 illustrates a pulse generator stage 900 which may be used as oneof the pulse generator stages 810, 820, and 830 of pulse generatorcircuit 800 shown in FIG. 8.

Pulse generator stage 900 receives trigger pulses across input porttrigger input (i.e., the voltage between the + and − terminals of thetrigger input), and generates output voltages at output port Vout inresponse to the received trigger pulses. The output voltages are alsogenerated based on power voltages received at power input terminals V1and V2. Pulse generator stage 900 includes multiple switch drivers 950.Pulse generator stage 900 also includes switch stack 910, capacitor 920,and resistors 930 and 940.

Switch drivers 950 are configured to receive the trigger pulses, and togenerate control signals for the switches of switch stack 910 inresponse to the received trigger pulses, as discussed in further detailbelow. Each of the control signals is referenced to a voltage specificto the switch being driven. Accordingly, a first switch receives acontrol signal pulse between first and second voltages, and a secondswitch receives a control signal pulse between third and fourthvoltages, where each of the first, second, third, and fourth voltagesare different. In some embodiments, the difference between the first andsecond voltages is substantially the same as the difference between thethird and fourth voltages.

Switch stack 910, capacitor 920, and resistors 930 and 940 cooperativelyfunction with corresponding elements in the other pulse generator stagesof pulse generator circuit 800, discussed above with reference to FIG.8, to generate the voltage pulses across the positive and negative Vooutput terminals of pulse generator circuit 800. These elements may, forexample, cooperatively function as the corresponding elements discussedabove with reference to pulse generator circuit 500 shown in FIGS. 5,6A, and 6B. For example, these elements may cooperate to generate thevoltage pulses across the positive and negative Vo output terminals ofpulse generator circuit 800 in response to the power voltages applied topower input terminals V1 and V2 and to the control signals applied tothe switches of switch stack 910.

Because the control signals are generated in response to the inputpulses received across input port Vin of pulse generator circuit 700illustrated in FIG. 7 through multiple stages of driving, the controlsignals cause all of the switches of the switch stacks of pulsegenerator circuit 700 to be turned on and to be turned off substantiallysimultaneously. For example, a 15V input pulse having a duration of, forexample 100 ns, received at input port Vin of pulse generator circuit700 may cause the pulse generator circuit 700 to generate a high-voltage(e.g. ˜15 kV) output pulse having a duration of about 100 ns. Similarly,a 15V input pulse having a duration of, for example 5 μs, received atinput port Vin of pulse generator circuit 700 may cause the pulsegenerator circuit 700 to generate a high-voltage (e.g. ˜15 kV) outputpulse having a duration of about 5 μs. Accordingly, the duration of thehigh-voltage output pulse is substantially the same as a selectedduration of an input pulse.

FIG. 10 illustrates a switch driver 1000 which may be used as one of theswitch drivers shown in FIG. 9.

Switch driver 1000 receives trigger pulses across input port Vin, andgenerates control signal pulses at output port Vout in response to thereceived trigger pulses. Switch driver 1000 includes amplifier circuit1010, capacitor 1020, and transformer 1030. In some embodiments, switchdriver 1000 also includes clamps circuits 1070.

Amplifier circuit 1010 receives the trigger pulses, and drivestransformer 1030 through capacitor 1020, which reduces or blocks lowfrequency and DC signals. In response to being driven by amplifiercircuit 1010, transformer 1030 generates control signal pulses acrossresistor 1070 at output port Vout, such that the duration of the controlsignal pulses is equal to or substantially equal (e.g. within 10% or 1%)to the duration of the trigger pulses at input port Vin.

In some embodiments, amplifier circuit 1010 includes multiple amplifierintegrated circuits. For example, for increased current drivingcapability, multiple amplifier integrated circuits may be connected inparallel to form amplifier circuit 1010. For example, 2, 3, 4, 5, 6, 7,8 or another number of amplifier integrated circuits may be used.

In some embodiments, clamp circuits 1070 are included at least to dampenpotential signals, which may otherwise be caused by resonance. Clampcircuits 1070 include parallel diodes, which provide a short-circuitpath for any current reversal, and also clamp the maximum voltage acrossthe components connected to the clamp circuits 1070.

In some embodiments, the drivers 750, 850, and 1000 receive power from aDC-DC power module which is isolated from the power supply for the Marxgenerator. This ensures the cutoff of ground coupling.

In some embodiments, transformer 1030 has a 1:1 turns ratio. Inalternative embodiments, a different turns ratio is used.

In some embodiments, in order to obtain very fast switching, thetransformers 1030 has fewer than 5 turns in the primary winding andfewer than 5 turns in the secondary winding. For example, in someembodiments, the transformer 1030 has 1, 2, 3, or 4 turns in each of theprimary and secondary windings. In some embodiments, the transformer1030 has less than a complete turn, for example, ½ turn in the primaryand secondary windings. The low number of turns in each of the primaryand secondary windings allows for a low inductance loop and increasesthe current risetime in the secondary winding, which charges the inputcapacitance of the MOSFET switches.

Transformers for triggering MOSFETs in conventional applications requirehigh coupling, high permeability, and a low-loss core in order to ensurecurrent transfer efficiency. From pulse to pulse, the residual flux inthe core needs to be cleared in order to avoid saturation when thetransformer is operated at high frequency. Conventionally, a resettingcircuit, which involves a third winding, to dissipate the core energy isused.

In some embodiments, lossy transformers, such as that typically used asan electromagnetic interference (EMI) choke to confine high frequencysignals and dissipate their energy as heat are used to trigger theswitches. For example, the transformers may have a voltage time constantless than 100Vμs. In some embodiments, the Transformers have a voltagetime constant less than 50Vμs, 30Vμs, 20Vμs, 10Vμs, or 5Vμs. The use ofthe lossy transformer is contrary to the common practice in powerelectronics.

Although the high frequency flux is dampened due to the loss of the core(eddy loss, hysteresis loss, and resistive loss), the lossy transformersstill allow sufficient confinement of the magnetic flux and providessufficient coupling. In addition, the flux also decreases quicklyenough. The flux decay process usually takes approximately severalmicroseconds.

Having such a transformer conventionally seems disadvantageous, but forcoupling nanosecond to a few microsecond pulses, such a transformer ispreferably used. Consequently, the following benefits are achieved: 1)high voltage, high frequency transient coupling from the high-voltageMarx generators to the low-voltage drivers is suppressed; 2) because ofthe loss in the transformer cores, the residual flux from previouspulses are dissipated faster than common low-loss transformer cores,such that the resetting winding is not needed and is not present.

A benefit of the switch driver 1000 is that it limits the output pulseduration. Because the switch control signals are generated bytransformer 1030, even if circuitry generating the input trigger signalsat input port Vin were to generate a pulse of indefinite length, thetransformer would saturate, causing the control signals to turn off theswitches.

FIG. 11 illustrates an example of a switch element 1100 comprisingcomponents which may be used in the switch stacks discussed here. Switchelement 1100 includes switch 1110, and selectively forms a conductive orlow resistance path between terminals VA and VB in response to a controlvoltage applied to input port Vin.

In some embodiments, switch 1110 is a transistor, such as a MOSFET. Insome embodiments, switch 1110 is another type of switch. In someembodiments, switch 1110 has a turn on time of less than 5 ns, about 5ns, about 10 ns, about 25 ns, about 15 ns, about 75 ns, about 100 ns, orgreater than 100 ns.

In some embodiments, switch element 1100 also includes snubber circuit1120. In some embodiments, the turn on times of the switches of theswitch stacks are not identical. In order to prevent voltages greaterthan that which switch 1110 can tolerate, snubber circuit 1120 providesa current shunt path bypassing switch 1110. Diodes 1122 provide alow-frequency current path, and the combination of the capacitor 1126and resistor 1124 provide a high-frequency current path.

In some embodiments, switch element 1100 also includes optionalovercurrent protection circuit 1140. Overcurrent protection circuit 1140includes switch 1142 and sense resistor 1144.

Current flowing from terminal VA to terminal VB is conducted throughsense resistor 1144. Diodes 1132 and 1134 are each in parallel.Accordingly, a voltage is generated across sense resistor 1144 when thecurrent flows from terminal VA to terminal VB. The generated voltagecontrols a conductive state of switch 1142. If the current flowing fromterminal VA to terminal VB is greater than a threshold, the generatedvoltage causes the switch 1142 to conduct. As a result, switch 1142reduces the control voltage of switch 1110. In response to the reducedcontrol voltage, switch 1110 becomes less conductive or turns off.Consequently, the current which may be conducted from terminal VA toterminal VB is limited by overcurrent protection circuit 1140.

In the embodiments discussed herein, MOSFET switches are used. Inalternative embodiments, other switches are used. For example, in someembodiments, thyristors, IGBTs or other semiconductor switches are used.

An example of the operation of the transformer is illustrated in FIG.12. The voltage at the input primary inductor is substantially a squarewaveform, but the voltage at the secondary inductor, which is theMOSFET's gate-source voltage, tapers as the voltage magnitude decreasestoward zero, for example, within a period of several microseconds. Aftera reduction in voltage at the secondary inductor, the switch receivingthe voltage enters a linear region of operation from a saturation regionof operation when the voltage is lower than the fully enhanced Vgs. As aresult, the resistance of the switch increases and the output voltageacross the load also shows a tapered profile. When the voltage at thesecondary inductor decreases to a value less than the turn-on thresholdof a MOSFET (Vth), the MOSFET will be shut off. Once the MOSFET is off,even if the duration of the trigger signal is extended, the voltage atthe load goes to zero. The waveform of the voltage at the secondaryinductor therefore limits the duration of high voltage output pulsesfrom each panel, for example, to be several microseconds or less.

In some embodiments, the duration of the trigger signal is short enoughthat the switches remain in saturation because the reduction in voltageat the secondary inductor is insufficient to cause the switches to enterlinear region operation. In such embodiments, the load voltage pulses donot exhibit the tapering illustrated in FIG. 12. For example, in suchembodiments the load voltage pulses may be substantially square.

In some embodiments, the switch stacks discussed herein includeswitches, as discussed above, as well as other components.

In some embodiments, when generating pulses of a duration less than athreshold, the shape of the pulses are substantially square. In someembodiments, when generating pulses of the duration greater than athreshold, the shape of the pulses are substantially square for aduration substantially equal (e.g. within 10% or 1%) to the threshold.During the time after the threshold, the voltage of such long pulsesdrops toward 0 V. In some embodiments, the drop toward 0 V issubstantially linear. In some embodiments, the drop toward 0 V issubstantially exponential.

FIG. 13 illustrates an alternative pulse generator circuit 1300 whichmay be used inside nsPEF system 100 of FIG. 1.

Pulse generator circuit 1300 receives input pulses across input port Vinand DC voltages at input ports VDC1 and VDC2, and generates outputpulses across output port Vout in response to the received input pulsesand DC voltages.

Pulse generator circuit 1300 includes multiple pulse generator circuits1310 and 1320. In this embodiment, two pulse generator circuits areused. In alternative embodiments, more pulse generator circuits areused. For example, in some embodiments, 3, 4, 5, 10 or another number ofpulse generator circuits having their output ports serially connected,as discussed below with reference to pulse generator circuit 1300, areused.

Each of pulse generator circuits 1310 and 1320 may be similar to theother pulse generator circuits discussed herein. For example pulsegenerator circuits 1310 and 1320 may be similar to or may besubstantially identical to pulse generator circuit 700 discussed abovewith reference to FIG. 7.

Each of pulse generator circuits 1310 and 1320 receive the same inputpulse signal across their respective Control In input ports. Inresponse, each of pulse generator circuits 1310 and 1320 generate highvoltage pulses across their respective Vout output ports. Because theVout output ports of pulse generator circuits 1310 1320 are seriallyconnected, the voltage pulse generated by pulse generator circuits 1310and 1320 across output port Vout of pulse generator circuit 1300 issubstantially equal (e.g. within 10% or 1%) to the sum of the voltagesof the pulses respectively generated by pulse generator circuits 1310and 1320.

FIG. 14 illustrates an alternative pulse generator circuit 1400 whichmay be used inside nsPEF system 100 of FIG. 1, and which hascharacteristics similar to the pulse generator 1300 of FIG. 13. Pulsegenerator circuit 1400 includes pulse generators 1410 and 1420, drivers1415 and 1425, and power supplies 1412 and 1422.

Pulse generator circuit 1400 includes multiple pulse generator circuits1410 and 1420. In this embodiment, two pulse generator circuits areused. In alternative embodiments, more pulse generator circuits areused. Each of pulse generator circuits 1410 and 1420 may be similar tothe other pulse generator circuits discussed herein.

Pulse generator circuit 1400 receives input pulses at each of drivers1415 and 1425, which may be similar to driver 850 discussed above withreference to FIG. 8. Pulse generator circuit 1400 generates outputpulses across output port Vout in response to the received input pulses.The output voltage pulses are also based on power voltages received frompower supplies 1412 and 1422.

Each of drivers 1415 and 1425 receive an input pulse signal. In responseto the received input signals, drivers 1415 and 1425 respectivelygenerate driving signal pulses for pulse generator circuits 1410 and1420. In response to the driving signal pulses, each of pulse generatorcircuits 1410 and 1420 generate high voltage pulses across theirrespective output ports Vo1 and Vo2. Because the Vo1 and Vo2 outputports of pulse generator circuits 1410 and 1420 are serially connected,the voltage pulse generated by pulse generator circuits 1410 and 1420across output port Vout of pulse generator circuit 1400 is substantiallyequal (e.g. within 10% or 1%) to the sum of the voltages of the pulsesrespectively generated by pulse generator circuits 1410 and 1420.

In this embodiment, pulse generator circuit 1410 generates a highvoltage pulse across its output port Vo1 which is substantially equal(e.g. within 10% or 1%) to three times the voltage of power supply 1412,(−3×[V1−V2]). In addition, pulse generator circuit 1420 generates a highvoltage pulse across its output port Vo2 which is substantially equal(e.g. within 10% or 1%) to three times the voltage of power supply 1414(3×[V′1−V′2]). As a result, pulse generator circuit 1400 generates avoltage of (3×[V′1−V′2])−(−3×[V1−V2]) across its output port Vout.

In some embodiments, a single driver circuit connected to both pulsegenerator circuit 1410 and 1420 is used instead of drivers 1415 and1425. In such embodiments, the single driver circuit generates drivingsignal pulses for both pulse generator circuits 1410 and 1420 inresponse to an input pulse signal.

FIG. 15 is a block diagram of a nsPEF treatment system 1550, which hascharacteristics similar to or identical to those of nsPEF system 100illustrated in FIG. 1. NsPEF treatment system 1550 includes pulsegenerator 1555, power supply 1560, electrode 1565, interface 1570, andcontroller 1575.

Pulse generator 1555 may be similar or identical to any of the pulsegenerator circuits discussed herein. For example, pulse generator 1555may be configured to generate pulses having a voltage magnitudecorresponding with power voltages received from power supply 1560 andhaving pulse widths and other characteristics corresponding with controlsignals received from controller 1575. In alternative embodiments, otherpulse generator circuits may be used.

Electrode 1565 may be similar or identical to any of the electrodesdiscussed herein. For example, electrode 1565 may be similar oridentical to electrodes 300 and 400 discussed above with reference toFIGS. 3 and 4. Electrode 1565 is configured to receive nsPEF pulsesgenerated by pulse generator 1555 from conductor 1556 and is configuredto deliver nsPEF pulses to a patient undergoing therapeutic nsPEFtreatment. In alternative embodiments, other therapeutic electrodes maybe used.

Power supply 1560 is configured to provide power voltages to pulsegenerator 1555. For example, in embodiments where pulse generator 1555is similar to pulse generator circuit 700 illustrated in FIG. 7, powersupply 1560 may be configured to provide power voltages correspondingwith power voltages V1 and V2 of pulse generator circuit 700. In someembodiments, power supply 1560 generates and provides power voltageswhich have a voltage level corresponding with a control signal fromcontroller 1575.

Interface 1570 is configured to receive input from a user identifyingvarious parameters and characteristics of the nsPEF pulses to be appliedto the patient. For example, interface 1570 may be configured to receiveinput identifying or specifying values for one or more characteristicsof one or more nsPEF pulses to be applied to the patient. For example,the characteristics may include one or more of an amplitude, a polarity,a width, a rise time, and a fall time of one or more nsPEF pulses to beapplied to the patient. Additionally or alternatively, thecharacteristics may include one or more of a frequency and a pulsequantity of a sequence of nsPEF pulses to be applied to the patient.Furthermore, the characteristics may additionally or alternativelyinclude a result of the nsPEF pulses to be applied to the patient, suchas a maximum temperature for the treated tissue of the patient. Othercharacteristics may additionally or alternatively be identified orspecified by the received input.

In addition, interface 1570 is configured to communicate thecharacteristics identified or specified by the received input tocontroller 1575.

Controller 1575 is configured to generate and provide one or morecontrol signals to pulse generator 1555 and to power supply 1560 basedat least partly on the communicated characteristics received frominterface 1570. Additionally, pulse generator 1555, power supply 1560,and electrode 1565 are collectively configured to, in response to thecontrol signals from controller 1575, generate nsPEF pulses havingcharacteristics corresponding with the control signals.

In this embodiment, one or both of pulse generator 1555 and electrode1565 are configured to generate feedback signals FB1 and FB2corresponding with or representing measured parametric characteristicsof the nsPEF pulses applied to the patient. In some embodiments, theparametric characteristics of the nsPEF pulses represented by thefeedback signals FB1 and FB2 include one or more of an amplitude, apolarity, a width, a rise time, and a fall time of the nsPEF pulses.Additionally or alternatively, the parametric characteristics mayinclude a frequency of a sequence of nsPEF pulses. Furthermore, theparametric characteristics may additionally or alternatively include atemperature of the treated tissue of the patient. The feedback signalsFB1 and FB2 may correspond or represent other measured parametriccharacteristics of one or more of the nsPEF pulses applied to thepatient, the patient, the environment, and the nsPEF treatment system1550.

In some embodiments, controller 1575, power supply 1560, pulse generator1555, and electrode 1565 collectively form a feedback loop which causesone or more parametric characteristics of the nsPEF pulses applied tothe patient to have measured values substantially equal (e.g. within 10%or 1%) to the values of corresponding characteristics identified in theinput received by interface 1570.

For example, interface 1570 may receive input specifying a value of 15kV for an amplitude of the nsPEF pulses applied to the patient. Inaddition, the controller 1575 may be configured to, in response to afeedback signal FB2 from electrode 1565 or a feedback signal FB1 frompulse generator 1555 indicating that the measured amplitude of the nsPEFpulses applied to the patient is less than (or greater than) 15 kV,change a control signal provided to power supply 1560. In response tothe changed control signal, power supply 1560 may be configured toincrease (or decrease) the voltage of power signals provided to pulsegenerator 1555 such that the amplitude of the nsPEF pulses generated andapplied to the patient increases (or decreases) to or toward 15 kV.

Similarly, interface 1570 may receive input specifying a value of 150 nsfor a pulse width of the nsPEF pulses applied to the patient. Thecontroller 1575 may be configured to, in response to a feedback signalFB2 from electrode 1565 or a feedback signal FB1 from pulse generator1555 indicating that the measured pulse width of the nsPEF pulsesapplied to the patient is greater than (or less than) 150 ns, change acontrol signal provided to pulse generator 1555. In response to thechanged control signal, pulse generator 1555 may be configured togenerate and apply to the patient nsPEF pulses having decreased (orincreased) pulse width. As a result, the feedback signal FB1 or FB2causes the controller 1575 to generate control signals which cause thepulse generator 1555 to generate and apply nsPEF pulses having pulsewidths decreased (or increased) to or toward 150 ns.

In some embodiments, the feedback loop is controlled using aProportional-Integral-Derivative (PID) method. For example, controller1575 may be configured to continuously or substantially continuouslycalculate an error value as the difference between a desired valueperceived at interface 1570 and a corresponding measured parameter. Inaddition, controller 1575 may be configured to continuously orsubstantially continuously calculate the control signals as a sum of oneor more of: a first constant times the error signal, a second constanttimes an integral of the error signal, and a third constant times aderivative of the error signal.

In some embodiments, the feedback loop is controlled using a lookuptable to determine a next value based on a measured value. In someembodiments, the feedback loop is controlled by reducing or increasing avalue by a fixed amount or step size based on a determination of whethera measured value is greater than or less than a threshold.

FIG. 16 illustrates an alternative pulse generator 1600 which may beused as pulse generator 1555 of nsPEF treatment system 1550 illustratedin FIG. 15. Pulse generator 1600 may have features similar to oridentical to other pulse generator circuits discussed herein. Forexample, pulse generator circuit 1600 may have features similar to oridentical to pulse generator circuit 700 of FIG. 7.

For example, pulse generator 1600 includes the driver circuit 1650 whichmay be similar to or identical to driver 750 of pulse generator circuit700. In addition, pulse generator 1600 includes pulse generator circuits1610, 1620, 1630, and 1640, which may respectively be similar oridentical to pulse generator circuits 710, 720, 730, and 740.

Pulse generator 1600 also includes, or in some embodiments is connectedto, analog-to-digital converter 1660. Furthermore, pulse generator 1600additionally or alternatively includes, or in some embodiments isconnected to, current monitors 1670 and 1680.

In this embodiment, analog-to-digital (A/D) converter 1660 includes afirst channel having inputs which are respectively connected to thepositive (+) and negative (−) voltage output terminals of pulsegenerator 1600. In some embodiments, a first low input impedancedifferential buffer (not shown) is connected to the positive (+) andnegative (−) voltage output terminals of pulse generator 1600, anddrives the inputs of analog-to-digital converter 1660. In someembodiments, a probe, such as a Tektronix P6015A Passive High VoltageProbe (not shown) is connected to the positive (+) and negative (−)voltage output terminals of pulse generator 1600, and drives the inputsof analog-to-digital converter 1660.

In addition, analog-to-digital converter 1660 is configured to generatea first digital output representing the voltage difference between thepositive (+) and negative (−) voltage output terminals of pulsegenerator 1600. When used in the nsPEF treatment system 1650 of FIG. 15,the first digital output may be used as a feedback signal for controller1575. In some embodiments, analog-to-digital converter 1660 generatesthe first digital output based on either, but not both, of the voltagesat the positive (+) and negative (−) voltage output terminals.

In this embodiment, analog-to-digital converter 1660 also includes asecond channel having inputs which are respectively connected to thecurrent monitors 1670 and 1680, and the current monitors 1670 and 1680are respectively connected to the positive (+) and negative (−) voltageoutput terminals of pulse generator 1600. In some embodiments, a secondlow input impedance differential buffer (not shown) is connected to thecurrent monitors 1670 and 1680, and drives the inputs ofanalog-to-digital converter 1660.

In addition, analog-to-digital converter 1660 is configured to generatea second digital output representing the current difference between thecurrents flowing through positive (+) and negative (−) voltage outputterminals of pulse generator 1600. When used in the nsPEF treatmentsystem 1550 of FIG. 15, the second digital output may be used as afeedback signal for controller 1575. In some embodiments,analog-to-digital converter 1660 generates the second digital outputbased on either, but not both, of inputs from the current monitors 1670and 1680.

In some embodiments, current monitors 1670 and 1680 each include a senseresistor and an amplifier. The sense resistor is configured to generatea voltage response of the current flowing therethrough, and theamplifier generates an input for the analog-to-digital converter basedon the voltage across the sense resistor.

In some embodiments, current monitors 1670 and 1680 include a currentmonitor, such as Pearson Current Monitor 2878, which generates a voltagein response to a sensed current.

In some embodiments, pulse generator 1600 generates either, but notboth, of the first and second digital outputs. In some embodiments, oneor more single channel analog-to-digital converters are used instead ofor in addition to analog-to-digital converter 1660.

FIG. 17 is a schematic illustration of an electrode 1700 which may, forexample, be used as electrode 1565 in nsPEF treatment system 1550 ofFIG. 15. Electrode 1700 may be similar or identical to any of theelectrodes discussed herein. For example, electrode 1700 may be similaror identical to electrodes 300 and 400 discussed above with reference toFIGS. 3 and 4.

Electrode 1700 is configured to receive nsPEF pulses across inputterminals 1710 and 1720 and to deliver nsPEF pulses to a patientundergoing therapeutic nsPEF treatment through positive (+) and negative(−) output therapeutic electrode terminals 1730 and 1740.

Electrode 1700 includes, or in some embodiments is connected to,analog-to-digital converter 1750. Furthermore, electrode 1700additionally or alternatively includes, or in some embodiments isconnected to, current monitors 1760 and 1770. In addition, electrode1700 includes thermal sensors 1780 and 1790. In some embodiments,electrode 1700 includes either but not both of thermal sensors 1780 and1790.

In this embodiment, analog-to-digital converter 1750 includes a firstchannel having inputs which are respectively connected to the positive(+) and negative (−) voltage output therapeutic electrode terminals 1730and 1740. In some embodiments, a first low input impedance differentialbuffer (not shown) is connected to the positive (+) and negative (−)voltage output therapeutic electrode terminals 1730 and 1740 and drivesthe inputs of the first channel of analog-to-digital converter 1750. Insome embodiments, a probe, such as a Tektronix P6015A Passive HighVoltage Probe (not shown) is connected to the positive (+) and negative(−) voltage output therapeutic electrode terminals 1730 and 1740, anddrives the inputs of analog-to-digital converter 1750.

In addition, analog-to-digital converter 1750 is configured to generatea first digital output at output terminal 1735 representing the voltagedifference between the positive (+) and negative (−) voltage outputtherapeutic electrode terminals 1730 and 1740. When used in the nsPEFtreatment system 1650 of FIG. 15, the first digital output may be usedas a feedback signal for controller 1575. In some embodiments,analog-to-digital converter 1750 generates the first digital outputbased on either, but not both, of the voltages at the positive (+) andnegative (−) voltage output therapeutic electrode terminals 1730 and1740.

In this embodiment, analog-to-digital converter 1750 also includes asecond channel having inputs which are respectively connected to thecurrent monitors 1760 and 1770, and the current monitors 1760 and 1770are respectively connected to the positive (+) and negative (−) voltageoutput therapeutic electrode terminals 1730 and 1740. In someembodiments, a second low input impedance differential buffer (notshown) is connected to the current monitors 1760 and 1770 and drives theinputs of the second channel of analog-to-digital converter 1750.

In addition, analog-to-digital converter 1750 is configured to generatea second digital output at output terminal 1765 representing the currentdifference between the currents flowing through positive (+) andnegative (−) voltage output therapeutic electrode terminals 1730 and1740. When used in the nsPEF treatment system 1550 of FIG. 15, thesecond digital output may be used as a feedback signal for controller1575. In some embodiments, analog-to-digital converter 1750 generatesthe second digital output based on either, but not both, of inputs fromthe current monitors 1760 and 1770.

In this embodiment, analog-to-digital converter 1750 also includes athird channel having inputs which are respectively connected to thethermal sensors 1780 and 1790, and the thermal sensors 1780 and 1790 arerespectively thermally coupled to the positive (+) and negative (−)voltage output therapeutic electrode terminals 1730 and 1740. In someembodiments, a third low input impedance differential buffer (not shown)is connected to the thermal sensors 1780 and 1790, and drives the inputsof the third channel of analog-to-digital converter 1750.

In addition, analog-to-digital converter 1750 is configured to generatea third digital output at output terminal 1785 representing atemperature of at least one of positive (+) and negative (−) voltageoutput therapeutic electrode terminals 1730 and 1740. When used in thensPEF treatment system 1550 of FIG. 15, the third digital output may beused as a feedback signal for controller 1575. In some embodiments,analog-to-digital converter 1750 generates the third digital outputbased on either, but not both, of inputs from the thermal sensors 1780and 1790.

In various embodiments, pulse generator 1700 generates any one, two, orall of the first, second, and third digital outputs. In someembodiments, one or more single channel analog-to-digital converters areused instead of or in addition to analog-to-digital converter 1750.

FIG. 18 is a flowchart illustration of a method 1800 of using an nsPEFtreatment system, such as nsPEF treatment system 1550 of FIG. 15. In themethod, the nsPEF treatment system implements a feedback loop to controla parameter of the treatment. Because of one or more factors including,but not limited to, manufacturing variation, temperature, and systemage, realized or measured parameters during treatment tend to havevalues somewhat different from the corresponding values with which thesystem was programmed. To increase accuracy of the system, the feedbackloop actively measures and controls realized parameters so that themeasured parameters more closely match the desired or programmed values.

At 1810, information representing one or more desired characteristics ofa patient or of nsPEF pulses to be applied to the patient is received atan interface, such as interface 1570 of nsPEF treatment system 1550.

At 1820, a controller, such as controller 1575 of nsPEF treatment system1550, generates control values corresponding with the values of thedesired characteristics received at the interface.

At 1830, a power supply, such as power supply 1560 of nsPEF treatmentsystem 1550, charges a pulse generator, such as pulse generator 1555 ofnsPEF treatment system 1550. The power supply charges the pulsegenerator with a voltage value determined based on one or more controlsignals received from the controller, where the received one or morecontrol signals correspond with one or more control values generated at1820.

At 1840, at least one nsPEF pulse is generated. In some embodiments, theat least one generated nsPEF pulse is applied to the patient. Forexample, in response to one or more control signals from the controller,the pulse generator may generate the nsPEF pulse. In addition, anelectrode, such as electrode 1565, may apply the nsPEF pulse to thepatient. In some embodiments, the nsPEF pulse is applied to the patientas part of a treatment regimen. In some embodiments, the nsPEF pulse isapplied to the patient as part of a characterization, set up, orcalibration of the nsPEF treatment system. In some embodiments, thensPEF pulse is not applied to the patient.

At 1850, one or more electrical characteristics of the nsPEF pulse or ofthe patient are measured or sensed, for example, while the nsPEF pulseis applied to the patient.

At 1860, a value of the measured or sensed characteristic is comparedwith the value of a corresponding desired characteristic as representedby the received information at 1810.

Returning to 1820, the controller modifies the control valuescorresponding with the values of the desired characteristics received atthe interface according to the results of the comparison performed at1860. The controller is configured to modify the control values so that,because of the modification to the control value, the value of a nextmeasured or sensed characteristic is expected to be closer to thedesired value of the characteristic than the value of the previouslymeasured or sensed characteristic.

FIG. 19 is a flowchart illustration of a method 1900 of using an nsPEFtreatment system, such as nsPEF treatment system 1550 of FIG. 15.

At 1910, information representing a current or voltage amplitude ofnsPEF pulses to be applied to the patient is received at an interface,such as interface 1570 of nsPEF treatment system 1550.

At 1920, a controller, such as controller 1575 of nsPEF treatment system1550, generates control values corresponding with the desired amplitude.

At 1930, a power supply, such as power supply 1560 of nsPEF treatmentsystem 1550, charges a pulse generator, such as pulse generator 1555 ofnsPEF treatment system 1550. The power supply charges the pulsegenerator with a voltage value determined based on one or more controlsignals received from the controller, where the received one or morecontrol signals correspond with one or more control values generated at1920.

At 1940, at least one nsPEF pulse is generated. In some embodiments, theat least one generated nsPEF pulse is applied to the patient. Forexample, in response to one or more control signals from the controller,the pulse generator may generate an nsPEF pulse. In addition, anelectrode, such as electrode 1565, may apply the nsPEF pulse to thepatient. In some embodiments, the nsPEF pulse is applied to the patientas part of a treatment regimen. In some embodiments, the nsPEF pulse isapplied to the patient as part of a characterization, set up, orcalibration of the nsPEF treatment system. In some embodiments, thensPEF pulse is not applied to the patient.

At 1950, the amplitude of the nsPEF pulse is measured or sensed, forexample, while the nsPEF pulse is applied to the patient.

At 1960, a value of the measured or sensed amplitude is compared withthe amplitude as represented by the received information at 1910.

Returning to 1920, the controller modifies the control valuescorresponding with the values of the desired amplitude received at theinterface according to the results of the comparison performed at 1960.The controller is configured to modify the control values so that if themeasured or sensed value of the amplitude is less than the desiredamplitude, the modified control values will cause the power supply tocharge the pulse generator with a voltage of greater value thanpreviously used. Likewise, the controller is additionally configured tomodify the control values so that if the measured or sensed value of theamplitude is greater than the desired amplitude, the modified controlvalues will cause the power supply to charge the pulse generator with avoltage of less value than previously used.

FIG. 20 is a flowchart illustration of a method 2000 of using an nsPEFtreatment system, such as nsPEF treatment system 1550 of FIG. 15.

At 2010, information representing a pulse width of nsPEF pulses to beapplied to the patient is received at an interface, such as interface1570 of nsPEF treatment system 1550.

At 2020, a controller, such as controller 1575 of nsPEF treatment system1550, generates control values corresponding with the desired pulsewidth.

At 2030, a power supply, such as power supply 1560 of nsPEF treatmentsystem 1550, charges a pulse generator, such as pulse generator 1555 ofnsPEF treatment system 1550. The power supply charges the pulsegenerator with a voltage value determined based on one or more controlsignals received from the controller.

At 2040, at least one nsPEF pulse is generated. In some embodiments, theat least one generated nsPEF pulse is applied to the patient. Forexample, in response to one or more control signals from the controller,the pulse generator may generate an nsPEF pulse. In addition, anelectrode, such as electrode 1565, may apply the nsPEF pulse to thepatient. In some embodiments, the nsPEF pulse is applied to the patientas part of a treatment regimen. In some embodiments, the nsPEF pulse isapplied to the patient as part of a characterization, set up, orcalibration of the nsPEF treatment system. In some embodiments, thensPEF pulse is not applied to the patient.

At 2050, the pulse width of the nsPEF pulse is measured or sensed, forexample, while the nsPEF pulse is applied to the patient.

At 2060, a value of the measured or sensed pulse width is compared withthe pulse width as represented by the received information at 2010.

Returning to 2020, the controller modifies the control valuescorresponding with the values of the desired pulse width received at theinterface according to the results of the comparison performed at 2060.The controller is configured to modify the control values so that if themeasured or sensed value of the pulse width is less than the desiredpulse width, the modified control values will cause the pulse generatorto generate further nsPEF pulses with a pulse width of greater valuethan previously generated. Likewise, the controller is configured tomodify the control values so that if the measured or sensed value of thepulse width is greater than the desired pulse width, the modifiedcontrol values will cause the pulse generator to generate further nsPEFpulses having a pulse width of less value than previously generated.

FIG. 21 is a flowchart illustration of a method 2100 of using an nsPEFtreatment system, such as nsPEF treatment system 1550 of FIG. 15.

At 2110, information representing a maximum tissue temperature of thepatient being treated with nsPEF pulses is received at an interface,such as interface 1570 of nsPEF treatment system 1550.

At 2120, a controller, such as controller 1575 of nsPEF treatment system1550, generates control values corresponding with the desired maximumtissue temperature.

At 2130, a power supply, such as power supply 1560 of nsPEF treatmentsystem 1550, charges a pulse generator, such as pulse generator 1555 ofnsPEF treatment system 1550. The power supply charges the pulsegenerator with a voltage value determined based on one or more controlsignals received from the controller.

At 2140, one or more nsPEF pulses are generated. In some embodiments,the generated nsPEF pulses are applied to the patient. For example, inresponse to one or more control signals from the controller, the pulsegenerator may generate the nsPEF pulses. In addition, an electrode, suchas electrode 1565, may apply the nsPEF pulses to the patient. In someembodiments, the nsPEF pulses are applied to the patient as part of atreatment regimen. In some embodiments, the nsPEF pulses are applied tothe patient as part of a characterization, set up, or calibration of thensPEF treatment system. In some embodiments, the nsPEF pulses are notapplied to the patient.

At 2150, the temperature of the patient is measured or sensed with atemperature sensor, for example, while the nsPEF pulses are applied tothe patient.

At 2160, a value of the measured or sensed temperature is compared withthe maximum temperature as represented by the received information at2110.

Returning to 2120, the controller modifies the control valuescorresponding with the values of the desired maximum temperaturereceived at the interface according to the results of the comparisonperformed at 2160. The controller is configured to modify the controlvalues so that if the measured or sensed value of the temperature isgreater than the maximum temperature or is greater than a threshold lessthan the maximum temperature, the modified control values will cause thensPEF treatment system to deliver less power to the patient. Forexample, the modified control values may cause nsPEF pulses having lesspulse width to be generated. Alternatively or additionally, the modifiedcontrol values may cause nsPEF pulses with lower frequency to begenerated.

FIG. 22 is an illustration of an electrode 2200 which may be used in thensPEF treatment systems discussed herein. For example, electrode 2200may be used to treat a patient with nsPEF pulses. Electrode 2200includes therapeutic electrode terminals 2219, which are electricallyconnected to cable 2230 through tip 2216 and handle 2214.

Electrode 2210 includes handle 2214 and removable, and in someembodiments, disposable, tip 2216. Several embodiments of tips 2216 areillustrated. Other embodiments are contemplated.

Tips 2216 include an electrically insulative portion 2218 and anelectrically conductive terminals 2219 configured to contact thepatient, for example by piercing tissue, and deliver nsPEF pulses to thepatient at the points of contact.

In some embodiments, insulative portion 2218 includes extensions 2218A,which each surround a portion of one of the electrically conductiveterminals 2219. In some embodiments, the lengths of the extensions 2218Aare adjustable with respect to the surface of insulative portion 2218from which they extend, such that the exposed portion of theelectrically conductive terminals 2219 is adjustable. In someembodiments, the lengths of the electrically conductive terminals 2219are additionally or alternatively adjustable with respect to thesurface.

As shown, the handle of 2214 includes finger stop 2215, which is spacedapart from high-voltage therapeutic terminals 2219 to help preventinadvertent contact between therapeutic terminals 2219 and a user'shands by keeping the user's hands spaced apart from the therapeuticterminals 2219 by a certain minimum distance as explained in more detaillater. In some embodiments, the distance is, for example, 0.85, 1.0,1.27, 2.5, 3.2, 3.8, 4.4, 5.1, 6.4, 7.6, 10.2, 12.7, or more centimeters(i.e., 0.33, 0.39, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, or moreinches).

In some embodiments, the exposed electrically conductive terminals 2219,which contact the patient, are adjustable. For example, a distance theconductive terminals 2219 extend from the insulative portions 2218 maybe adjustable. In some embodiments, the distance conductive terminals2219 extend from the insulative portion 2218 is controlled by movingconductive terminals 2219 with respect to insulative portion 2218, whichis fixed with respect to handle portion 2214. In some embodiments, thedistance conductive terminals 2219 extend from the insulative portion2218 is controlled by moving insulative portion 2218 with respect toconductive terminals 2219, which are fixed with respect to handleportion 2214.

Additionally or alternatively, a distance between adjacent conductiveterminals 2219 may be adjustable.

As shown, a handle portion of connector 2220 includes finger stop 2222,which is spaced apart from high-voltage conductive portion 2224 to helpprevent inadvertent contact conductive portion 2224 and a user's hands.

FIG. 23 is an illustration of an electrode 2300 which may be used in thensPEF treatment systems discussed herein. For example, electrode 2300may be used to treat a patient with nsPEF pulses. In this embodiment,electrically conductive terminals 2302 are spaced apart from one anotherby handle 2304, which is configured to apply a restorative force toterminals 2302 once displaced from a spaced apart neutral position. Forexample, handle 2304 may be configured to apply restorative force toterminals 2302 when terminals 2302 are spaced apart by a distancegreater than or less than 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 7.5 mm, 1 cm,1.5 cm, 2 cm, 2.5 cm, 3 cm, or another distance.

Handle 2304 includes handle feature 2306 to help prevent inadvertentcontact between terminals 2302 and a user's hands.

FIG. 24 is an illustration of an electrode 2400 which may be used in thensPEF treatment systems discussed herein. For example, electrode 2400may be used to treat a patient suffering from atrial fibrillation. Inthis embodiment, electrically conductive terminals 2410 and 2412 areadjustably spaced apart from one another according to a relativedistance between the thumb ring 2420 and finger grip 2430. In someembodiments, finger grip 2430 includes a ring configured to receive afinger of the user. Thumb ring 2420 includes ergonomic blunt surface2425 for engaging a palm of the user.

Electrode 2400 includes housing 2450 connected to terminals 2410 and2412 by shaft 2460. Housing 2450 includes a wiring channel toelectrically connect terminals 2410 and 2412 with cable 2465. In someembodiments, housing 2450 includes an internal stop (not shown)configured to ensure a minimum distance between terminals 2410 and 2412.In some embodiments, housing 2450 includes a spring and ratchetmechanism configured to lock terminals 2410 and 2412 at a fixeddistance. In such embodiments, housing 2450 also includes ratchetrelease button 2455 configured to selectively release terminals 2410 and2412 from a locked position.

In some embodiments, terminal 2410 is configured to move with respect tohousing 2450. In some embodiments, terminal 2412 is configured toadditionally or alternatively move with respect to housing 2450.

In some embodiments, shaft 2460 and terminals 2410 and 2412 each includea conduit configured to conduct a substance to the distal ends ofterminals 2410 and 2412. For example, an insulative gel may be extrudedfrom the ends of terminals 2410 and 2412 through the conduits.

FIG. 25 is an illustration of an electrode 2500 which may be used in thensPEF treatment systems discussed herein. For example, electrode 2500may be used during a laparoscopic procedure to treat a patient. In thisembodiment, electrically conductive terminals 2510 and 2512 areadjustably spaced apart from one another according to a relativedistance between the thumb ring 2520 and finger grip 2530.

Electrode 2500 includes housing 2550 connected to terminals 2510 and2512 by shaft 2560. Housing 2550 includes a wiring channel toelectrically connect terminals 2510 and 2512 with cable 2565. In someembodiments, housing 2550 includes an internal stop (not shown)configured to ensure a minimum clearance distance between terminals 2510and 2512. In some embodiments, housing 2550 includes a spring andratchet mechanism configured to lock terminals 2510 and 2512 at a fixeddistance. In such embodiments, housing 2550 also includes ratchetrelease button 2555 configured to selectively release terminals 2510 and2512 from a locked position.

In some embodiments, terminal 2510 is configured to move or rotate withrespect to shaft 2560. In some embodiments, terminal 2512 is configuredto additionally or alternatively move or rotate with respect to shaft2560. In some embodiments, terminals 2510 and 2512 are configured tomove with respect to shaft 2560 and with respect to each other such thatterminals 2510 and 2512 remain substantially parallel.

FIG. 26 is an illustration of instrument 2600 which may be used in thensPEF treatment systems discussed herein. For example, instrument 2600may be used, for example, as a catheter to contact the patent withterminals percutaneously or endoluminally during treatment. In thisembodiment, electrode 2620 is connected to endoscope 2610. For example,electrode 2620 may be routed through a lumen in the endoscope 2610.

Electrode 2620 includes insulative portion 2626 and positive andnegative electrically conductive terminals 2622. In some embodiments,electrode 2620 also includes needle 2628 to help electrode 2620penetrate through tissue.

Any of the electrodes discussed with reference to FIGS. 22-26 mayinclude a thermocouple thermally connected to either of its terminals.

FIGS. 27A and 27B are illustrations of a connector 2700 configured to bemated with a housing cutaway portion 2750. Connector 2700 may, forexample, be used in nsPEF system 100 to connect electrode 102 to housing105. When mated, connector 2700 electrically connects electrode 102 withthe electronic components internal to housing 105, such as an nsPEFpulse generator. FIG. 27A illustrates connector 2700 and cutaway portion2750 in an unmated position. FIG. 27B illustrates connector 2700 andcutaway portion 2750 in a mated position.

Connector 2700 includes a hole 2702 configured to receive a cableelectrically contacting an electrode. Connector 2700 also includes ahandle 2706 which includes internal conductors which electricallyconnect terminals 2704 with the cable. Handle 2706 can also include aninsulating safety structure, such as a standoff skirt 2708, which isconfigured to provide at least a minimum clearance distance d_(min_user)along a surface of connector 2700 between a user's hand holding theconnector 2700 by the handle 2706 (e.g., by a hand-grip portion of thehandle) and terminals 2704 without increasing the total length of theconnector 2700 or the actual physical distance between the terminals2704 and a location on the handle of the connector where the user mayplace his or her hands or fingers.

A “minimum clearance distance from the user's hands” (d_(min_user)) asused in the present disclosure includes a shortest distance that avoidsan arc both in the air or along an insulative material surface path to agrip portion for a user's hand. In other words, d_(min_user) includes adistance that is a greater of the following two distances: 1) a shortestdistance or path that prevents an arc between two conductive partsmeasured along any surface or combination of surfaces of an insulatingmaterial, and 2) a shortest path in air between two conductive partsthat prevents an arc. Addition of a standoff skirt, like the skirt 2708,also allows one to reduce the total length of the connector whileproviding a desired d_(min_user).

In some embodiments, the minimum clearance distance is equal to orgreater than 0.85, 1.0, 1.27, 2.5, 3.2, 3.8, 4.4, 5.1, 6.4, 7.6, 10.2,12.7, or more centimeters (i.e., 0.33, 0.39, 0.5, 1, 1.25, 1.5, 1.75, 2,2.5, 3, 4, 5, or more inches).

As shown, terminals 2704 are spaced apart from handle 2706 by spacers2710, for example, by a distance greater than 1 inch.

As shown, housing cutaway portion 2750 includes terminal receptacleholes 2752, which are configured to receive terminals 2704 of connector2700 when connector 2700 is mated with housing cutaway portion 2750. Inthis embodiment, housing cutaway portion 2750 also includes one or moreskirt receptacle holes 2754, which is configured to receive standoffskirt 2708 of connector 2700 when connector 2700 is mated with housingcutaway portion 2750.

To increase the distance of a shortest path along the surface ofconnector 2700 between electrically conductive terminals 2704 and theuser's hand, in this embodiment, standoff skirt 2708 includes twoconcentric ring portions. The concentric ring portions surround bothspacers 2710 and may be centered between the two spacers 2710. Inaddition, housing cutaway portion 2750 includes two skirt receptacleholes 2754. In alternative embodiments, a connector has just one or morethan two concentric ring portions and a corresponding housing cutawayportion has just one or more than two skirt receptacle holes.

FIGS. 28A, 28B, 28C, and 28D are illustrations of a cross-sectional viewof connector 2700 and housing cutaway portion 2750. The plane of thecross-sectional view is defined by the axis of the terminal receptacleholes 2752 illustrated in FIG. 27A. FIG. 28A illustrates connector 2700and cutaway portion 2750 in an unmated position. FIGS. 28B and 28Cillustrate connector 2700 and cutaway portion 2750 in a mated position,where FIG. 28C illustrates in detail F an enlarged view of portions ofconnector 2700 and cutaway portion 2750.

As shown in FIG. 28A, connector 2700 includes cavity 2720 configured toinclude wiring (not shown) which electrically connects the cable withterminals 2704. Cavity 2720 may also include wiring to connect to one ormore thermocouples connected to one or more of the terminals of theelectrode.

Housing cutaway portion 2750 includes female terminals 2760 (FIG. 28A)which are configured to receive male terminals 2704 when connector 2700and housing cutaway portion 2750 are in the mated position. Setbackdistance 2761 is from a face of housing 2750 to terminals 2760.

Cutaway portion 2750 also includes cavities 2770 which are configured toinclude wiring (not shown) which electrically connects terminals 2760with the electronic components internal to the housing. As a result,when in the mated position, the electronic components internal to thehousing are electrically connected with a therapeutic electrode viaterminals 2760, terminals 2704, wiring between terminals 2704 and acable, and the cable, which is electrically connected to the therapeuticelectrode.

Housing cutaway portion 2750 also illustrates electromechanical switch2780. As a result of connector 2700 and housing cutaway portion 2750being in the mated position, electromechanical switch 2780 assumes aconductive state indicating that the connector 2700 and the housingcutaway portion 2750 are mated. In addition, as a result of connector2700 and housing cutaway portion 2750 being in an unmaintained position,electromechanical switch 2780 assumes a conductive state indicating thatthe connector 2700 and the housing cutaway portion 2750 are unmated.Electromechanical switch 2780 may be connected to a controller (notshown) which may be configured to prevent electronic components internalto the housing from applying electrical signals to terminals 2760 as aresult of connector 2700 and housing cutaway portion 2750 being unmated,or may be configured to allow electronic components internal to thehousing to apply electrical signals to terminals 2760 as a result ofconnector 2700 and housing cutaway portion 2750 being mated.

In some embodiments, electromechanical switch 2780 includes circuitryconfigured to interface with the controller. For example, the controllermay identify the connector 2700 or an electrode connected to theconnector 2700 as a result of the controller receiving identifyinginformation from the circuitry. In some embodiments, the circuitry maybe configured to count and store the number of nsPEF pulses deliveredthrough the connector 2700.

FIG. 28D illustrate examples of minimum clearance distances. Femaleterminals 2760 provide electrical power to male plug terminals 2704.Terminals 2760 are shielded from or are spaced a minimum clearancedistance d_(min_user) 2898 apart from external portions of the housingwhich may be accessed by a hand or a finger of a user. The minimumclearance distance may be determined based at least in part on anexpected voltage applied to terminals 2760 to ensure that the voltage isinsufficient to cause a shock to a hand or finger of the user if placedthe minimum clearance distance from the terminals 2760.

Minimum clearance distance 2898 to the user is measured by followingsurfaces out of the receptacle's holes, around dual skirts 2708, and toa user, as a hand of a user may be placed next to a visible seam betweenthe connector 2700 when mated with the housing cutaway portion 2750 asshown. In some embodiments, the minimum clearance distance is at least0.85, 1.0, 1.27, 2.5, 3.2, 3.8, 4.4, 5.1, 6.4, 7.6, 10.2, 12.7, or morecentimeters (i.e., 0.33, 0.39, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5,or more inches).

FIG. 28D also shows an example of another minimum clearance distance2899, which represents minimum clearance distance between terminals(d_(min_terminals)). This distance d_(min_terminals) is described inmore detail in references to FIG. 29.

Either minimum clearance distance can be equal to or greater than 0.85,1.0, 1.27, 2.5, 3.2, 3.8, 4.4, 5.1, 6.4, 7.6, 10.2, 12.7, or morecentimeters (i.e., 0.33, 0.39, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5,or more inches).

FIG. 29 is an illustration of connector 2900 configured to be mated withhousing cutaway portion 2950. Connector 2900 may, for example, be usedin nsPEF system 100 to connect electrode 102 to housing 105. When mated,connector 2900 electrically connects electrode 102 with the electroniccomponents internal to housing 105, such as an nsPEF pulse generator.FIG. 29 illustrates connector 2900 and cutaway portion 2950 in anunmated position.

As a comparison of exemplary embodiments, FIG. 27 illustrates thefeatures and insulative structures of the present disclosure, such asthe skirt 2708, configured to provide a minimum clearance distancebetween the user's fingers and/or hand and the conductive terminals.FIG. 29 illustrates additional novel features configured to provide aminimum clearance distance 2899 between the conductive terminalsthemselves, such as a minimum clearance distance d_(min_terminals),shown in FIG. 28D. The minimum clearance distance d_(min_terminals)provides protection against an arc between the conductive terminals andprotects, for example, a patient.

The “minimum clearance distance between the terminals”(d_(min_terminals)) as used in the present disclosure includes ashortest distance that avoids an arc both in the air or along aninsulating material surface path. In other words, d_(min_terminals) caninclude a distance that is the greater of the following twodistances: 1) a shortest distance or path that prevents an arc betweentwo conductive parts measured along any surface or combination ofsurfaces of an insulating material, and 2) a shortest path in airbetween two conductive parts that prevents an arc.

A “creepage distance” include a shortest distance that prevents arcsalong the surface of the insulating material between two conductiveparts, as defined by the International Electrotechnical Commission(IEC), or as otherwise known in the art. It can include the surfacedistance from one conductive part to another conductive part or an areaaccessible by a user.

“Air clearance” includes the shortest path that prevents arc in airbetween two conductive parts as defined by the IEC, or as otherwiseknown in the art. It can include the uninterrupted distance through theair or free space from one conductive part to another conductive part oran area accessible by a user.

Connector 2900 can include features similar to or identical to connector2700 illustrated above in FIGS. 27A, 27B, 28A, 28B, and 28C.

Connector 2900 includes standoff skirt 2908, which is similar tostandoff skirt 2708 of connector 2700. In addition, connector 2900includes additional standoff skirts 2909. As shown, standoff skirts 2909each surround a portion of one of the spacers 2910. Standoff skirts 2909maintain a desired separation between terminals 2904.

Housing cutaway portion 2950 can include features similar to oridentical to housing cutaway portion 2750 illustrated above in it FIGS.27A, 27B, 28A, 28B, 28C, and 28D.

In this embodiment, in addition to terminal receptacle holes 2952 andskirt receptacle hole 2954, housing cutaway portion 2950 also includesskirt receptacle holes 2956, which are configured to receive skirts 2909of connector 2900 when connector 2900 is mated with housing cutawayportion 2950.

FIGS. 30A and 30B are illustrations of a cross-sectional view ofconnector 2900 and housing cutaway portion 2950. FIGS. 30A and 30Billustrate connector 2900 and cutaway portion 2950 in a mated position,where FIG. 30B illustrates in detail H an enlarged view of portions ofconnector 2900 and cutaway portion 2950.

In some embodiments, an nsPEF pulse generator may be connected with acable to a therapeutic electrode, where the therapeutic electrode hasterminals which are electrically connected to the cable by aconnector/receptacle mating having characteristics similar or identicalto one or more of connector 2700 and housing cutaway portion 2750 andconnector 2900 and housing cutaway portion 2950.

For example, FIGS. 31A and 31B illustrate an electrode 3100 which hastherapeutic terminals 3140 which are connected to cable 3150 throughconductors which run through electrode handle (or handle) 3110 andelectrode tip (or tip) 3120. Electrode 3100 may be used in the nsPEFtreatment systems discussed herein. For example, cable 3150 may beconnected to an nsPEF pulse generator by a connector (not shown) havingfeatures similar or identical to those of the connectors discussedelsewhere herein.

As shown, tip 3120 is removably connectable to handle 3110. To connecttip 3120 to handle 3110, connection terminals 3160 are inserted intoskirt 3130. In some embodiments, tip 3120 is disposable, or may bediscarded or disposed of after a single use.

FIGS. 32A, 32B, and 32C illustrate handle 3110, which includes handlebase 3210 and its housing 3212 and handle cap 3240. As shown in FIG.32B, cable 3150 extends into handle base 3210. First and second wires3260 split from cable 3150, and respectively extend through handle base3210 within the first and second wire bosses 3215 (see FIG. 32A). Eachof the first and second wires 3260 is connected, for example using asolder connection, with one of first and second connectors 3250 whichextend from the first and second wire bosses 3215.

First and second connectors 3250 are configured to receive connectionterminals 3160 from tip 3120. When tip 3120 is connected with handle3110, connection terminals 3160 extend into first and second connectors3250, causing a mechanical and an electrical connection to be madebetween connection terminals 3160 and cable 3150.

Because the voltage between connectors 3250 can be very large, leakagemay occur between connectors 3250 along a path on a surface orcombination of connected surfaces between connectors 3250, causing anarc. In some embodiments, first and second wires 3260 are surrounded byinsulation.

In some embodiments the electrode can be hand-held (e.g., it can includea hand-grip portion of the handle 3110), or otherwise it can be grabbedor contacted by a user's hand or fingers. Handle 3110 can also includean insulating safety structure, such as a standoff skirt, skirt hole,recess, or boss. The safety structure can be configured to provide atleast a minimum clearance distance d_(min_user) from electricalconnectors 3250 through internal mating surfaces, which may or may notbe glued together, to an outer surface where a user's hand might be.These safety structures may eliminate the need to increase the totallength of the handle 3110 or the actual physical distance between theconnectors 3250 and location on the handle where the user may place hisor her hands or fingers.

Handle 3110 can also include an insulating safety structure to provided_(min_terminals). This can take the form of skirts, skirt holes,notches, connector or wire channels, bosses, or other features. Forexample, connector channels 3245 provide additional clearance distancebetween connectors 3250 than if there were no such channels.

In some embodiments, the minimum clearance distance d_(min_terminals) isequal to or greater than 0.85, 1.0, 1.27, 2.5, 3.2, 3.8, 4.4, 5.1, 6.4,7.6, 10.2, 12.7, or more centimeters (i.e., 0.33, 0.39, 0.5, 1, 1.25,1.5, 1.75, 2, 2.5, 3, 4, 5, or more inches).

In some embodiments, one of the first and second wires 3260 is coveredby insulation, and the other of the first and second wires 3260 is notcovered by insulation. In such embodiments, to prevent or at leastminimize the leakage, the distance between the connector 3250 of thewire surrounded by insulation and the nearest portion of the wirewithout insulation along any path on any surface or combination ofsurfaces is equal to or greater than a minimum clearance distance. Insome embodiments, the minimum clearance distance is equal to or greaterthan 0.85, 1.0, 1.27, 2.5, 3.2, 3.8, 4.4, 5.1, 6.4, 7.6, 10.2, 12.7, ormore centimeters (i.e., 0.33, 0.39, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3,4, 5, or more inches).

As shown in FIG. 32B, handle cap 3240 can include skirt 3243, which hasconnector channels 3245. In addition, handle cap 3240 can include skirt3130 which includes terminal channels 3135.

When the handle 3110 is assembled, as shown in FIG. 32C, first andsecond wires 3260 within the first and second wire bosses 3215 and firstand second connectors 3250 extend through connector channels 3245 (seeFIG. 32B) of handle cap 3240. In addition, as shown in FIG. 32C, whenthe handle 3110 is assembled, connectors 3250 are exposed throughterminal channels 3135, such that when the handle 3110 is connected withtip 3120, the connection terminals of 3160 of the tip 3120 mechanicallyand electrically connect to connectors 3250.

In this embodiment, female connectors 3250 receive male connectionterminals 3160. In alternative embodiments, female connection terminals3160 receive male connectors 3250.

FIGS. 33A and 33B illustrate handle cap 3240. Handle cap 3240 includesexposed portion 3330 and insert portion 3340. As shown, handle cap 3240includes latch hook 3370. Latch hook 3370 is used to secure tip 3120 tohandle 3110. The connection of tip 3120 and handle 3110 is discussed infurther detail below.

FIGS. 34A and 34B illustrate handle base 3210. As shown, handle base3210 includes wire bosses 3215. Wire bosses 3215 are generally tubularwith the inner portion of the tubes each forming a wire channel 3410.The wire channels 3410 have openings 3415 at their ends which extendfrom handle base 3210 and are also open at slots extending along centralportions or sides of the wire bosses 3215. Wire channels 3410 areparticularly useful during assembly of handle 3110.

For example, during assembly a cable 3150 may be inserted into handlebase 3210 through the hole 3420. See FIGS. 32B and 34B. The cable 3150may be fed so as to extend beyond wire bosses 3215. Insulation may bestripped from cable 3150 so as to expose wires 3260. Connectors 3250 maybe connected, for example by soldering, to wires 3260. The cable 3150may be retracted from handle base 3210 such that connectors 3250 may beinserted into openings 3415 of wire bosses 3215. In addition, wires 3260may be run through wire channels 3410 of wire bosses 3215. In someembodiments, one or more of the cable 3150, the wires 3260, andconnectors 3250 may be cemented in place, for example, with epoxy. Insome embodiments, as part of the assembly process for handle 3110,handle base 3210 is cemented to handle cap 3240, for example, withepoxy.

FIGS. 35A and 35B illustrate tip 3120. As shown, tip 3120 includes tipbase 3510 and tip cap 3520. As shown, tip base 3510 and tip cap 3520house wires 3590 which electrically connect connection terminals 3160with therapeutic terminals 3140. When assembled, connection terminals3160 protrude from tip base 3510 through holes 3580, wires 3590 extendthrough tip base wiring channels 3570 and tip cap wiring channels 3525,and therapeutic terminals 3140 extend through tip cap holes 3560. Insome embodiments, one or more of the connection terminals 3160, wires3590, and therapeutic terminals 3140 may be cemented in place, forexample, with epoxy. In some embodiments, as part of the assemblyprocess for tip 3120, tip base 3510 is cemented to tip cap 3520, forexample, with epoxy.

As shown in FIG. 35B, tip base 3510 includes skirt holes 3515, which areconfigured to receive skirts 3517 of tip cap 3520 when tip base 3510 isconnected with tip cap 3520. In alternative embodiments, tip cap 3520has skirt holes configured to receive skirts of tip base 3510. In someembodiments each of tip cap 3520 and tip base 3510 have one skirt andone skirt hole, where the one skirt hole is configured to receive theskirt of the other of tip cap 3520 and tip base 3510. In someembodiments, a single skirt hole in either of tip cap 3520 and tip base3510 is configured to receive both skirts of the other of tip cap 3520and tip base 3510.

Because the voltage between therapeutic terminals 3140 can be verylarge, in some instances when proper insulation is missing and beforethe therapeutic terminals are inserted into a tissue, leakage may occurbetween therapeutic terminals 3140 along a path on an internal surfaceor combination of connected internal surfaces between therapeuticterminals 3140. To prevent or at least minimize the leakage, aninsulative structure may be incorporated into the design such as theskirts and skirt holes. Such structures are configured to provide orcause the minimum clearance distance d_(min_terminals) betweentherapeutic terminals 3140 along any internal path on any surface orcombination of surfaces. Such d_(min_terminals) can be equal to orgreater than 0.85, 1.0, 1.27, 2.5, 3.2, 3.8, 4.4, 5.1, 6.4, 7.6, 10.2,12.7, or more centimeters (i.e., 0.33, 0.39, 0.5, 1, 1.25, 1.5, 1.75, 2,2.5, 3, 4, 5, or more inches).

As shown in FIGS. 35A and 35B, tip base 3510 includes guard 3512. Guard3512 serves at least to help ensure that a user's hand remains a minimumclearance distance away from therapeutic terminals 3140. In someembodiments, the guard 3512 may be away from the therapeutic terminals3140, for example, by 0.85, 1.0, 1.27, 2.5, 3.2, 3.8, 4.4, 5.1, 6.4,7.6, 10.2, 12.7, or more centimeters (i.e., 0.33, 0.39, 0.5, 1, 1.25,1.5, 1.75, 2, 2.5, 3, 4, 5, or more inches).

As shown in FIGS. 35A and 35B, tip base 3510 includes skirt hole 3530,which is configured to receive skirt 3130 of handle 3110 when tip 3120is connected with handle 3110. In alternative embodiments, handle 3110has skirt holes configured to receive skirts of tip 3510. In someembodiments each of handle 3110 and tip 3510 have one skirt and oneskirt hole, where the one skirt hole is configured to receive the skirtof the other of handle 3110 and tip 3510. In some embodiments, a singleskirt hole in either of handle 3110 and tip 3510 is configured toreceive both skirts of the other of handle 3110 and tip 3510.

Tip 3120 can also include an insulating safety structure, such as astandoff skirt, recess, or boss. The safety structure can be configuredto provide at least a minimum clearance distance d_(min_user) fromterminals 3160 through internal mating surfaces, which may or may not beglued together, to an outer surface where a user's hand might be. Thesesafety structures may eliminate the need to increase the total length ofthe tip 3120 or the actual physical distance between the terminals 3160and location on the tip where the user may place his or her hands orfingers.

Tip 3120 can also include an insulating safety structure to provided_(min_terminals). This can take the form of skirts, notches, connectoror wire channels, bosses, or other features. For example, wiringchannels 3525 provide additional clearance distance between connectors3160 than if there were no such channels.

Because the voltage between connection terminals 3160 can be very large,leakage may occur between connection terminals 3160 along a path in theair or on a surface or combination of connected surfaces betweenconnection terminals 3160 causing an arc. To prevent or at least tominimize such potential arcs, insulative structures, such as skirts,skirt holes, bosses, and notches, lengthen the minimum clearancedistance d_(min_terminals) between connection terminals 3160 along anypath on any surface or combination of surfaces. In some embodiments, theminimum clearance distance is equal to or greater than 0.85, 1.0, 1.27,2.5, 3.2, 3.8, 4.4, 5.1, 6.4, 7.6, 10.2, 12.7, or more centimeters(i.e., 0.33, 0.39, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, or moreinches).

As shown in FIGS. 35A and 35B, tip cap 3520 includes fiducials 3550.Fiducials 3550 are radially aligned with a central point and may, forexample, indicate a geometric center of the therapeutic terminals 3140are particularly useful during therapeutic use of electrode 3100. Forexample, prior to use the desired location of treatment is determinedand marked with perpendicular lines which intersect at the desiredcenter point of treatment and which are long enough to extend beyond theelectrode fiducials 3550 when the electrode 3100 is positioned fortreatment. To properly place electrode 3100 for use on the desiredlocation, the user of electrode 3100 places electrode 3100 such thatfiducials 3550 align with the portion of the perpendicular lines whichextend beyond the fiducials 3550 of electrode 3100.

FIG. 36 illustrates tip base 3510. As shown, tip base 3510 includes tab3695 which has latch notch 3690. Tab 3695 and latch notch 3690 are usedto secure and to release the connection of tip 3120 and handle 3110. Theconnection of tip 3120 and handle 3110 is discussed in further detailbelow. Through holes 3580 are shown for where connectors will beinserted.

FIG. 37 illustrates tip cap 3520. As shown, tip cap 3520 includes holes3710, which are openings in skirts 3517 to tip cap wiring channels 3525(see FIG. 35B). In addition, tip cap 3520 includes therapeutic terminalholes 3560, through which therapeutic terminals 3140 extend, when tip3120 is assembled. In this embodiment, tip cap wiring channels 3525 havecross-sectional geometries which correspond with the arrays oftherapeutic terminals 3140. As a result, during assembly, when thetherapeutic terminals 3140 are fed through tip cap 3520, the therapeuticterminals 3140 align with therapeutic terminal holes 3560 in tip cap3520 because of the geometry of the therapeutic terminal arrays and thegeometry of the tip cap wiring channels 3525. In addition, in thisembodiment, therapeutic terminal holes 3560 collectively have geometriccharacteristics which correspond with corresponding embodiments oftherapeutic terminals 3140.

FIGS. 38-41 illustrate various embodiments of tip cap 3520. As shown,the tip caps 3520 of these embodiments include holes 3710, which areopenings to tip cap wiring channels 3525 (see FIG. 35B). In addition,tip caps 3520 of these embodiments include therapeutic terminal holes3560, through which therapeutic terminals 3140 extend, when tip 3120 isassembled. In these embodiments, tip cap wiring channels 3525 havecross-sectional geometries which correspond with the arrays oftherapeutic terminals 3140. As a result, during assembly, when thetherapeutic terminals 3140 are fed through tip cap 3520, the therapeuticterminals 3140 align with therapeutic terminal holes 3560 in tip cap3520 because of the geometry of the therapeutic terminal arrays and thegeometry of the tip cap wiring channels 3525. In addition, in theseembodiments, therapeutic terminal holes 3560 collectively have geometriccharacteristics which correspond with corresponding embodiments oftherapeutic terminals 3140.

In some embodiments, the therapeutic terminal holes 3560 collectivelyhave geometric characteristics which define a rectangle which is about10 mm×10 mm. Alternatively, the therapeutic terminal holes 3560 maycollectively have geometric characteristics which define a rectanglewhich is one of about 10 mm×5 mm, about 7.5 mm×5 mm, about 2.5 mm×5 mm,about 7.5 mm×7.5 mm, about 5 mm×10 mm, about 5 mm×5 mm, and about 2.5mm×2.5 mm. Other geometric arrangements may alternatively be used.

FIGS. 42A, 42B, and 42C illustrate electrode 3100 in an assembled statewith tip 3120 connected with handle 3110. As shown, tip 3120, whichincludes tip base 3510 and tip cap 3520, is connected with handle 3110,which includes handle base 3210 and handle cap 3240. Tip 3120 is securedto handle 3110 by a latch which has latch hook 3370 of handle cap 3240and latch notch 3690 in tab 3695 of tip base 3510. As shown in DETAIL B,latch hook 3370 is inserted in latch notch 3690 and prevents tip 3120from detaching from handle 3110.

To release tip 3120 from handle 3110, a force is exerted on tab 3695causing latch notch 3690 to move away from latch hook 3370, for example,by causing tab 3695 to flex. Once latch notch 3690 has moved enough thatlatch hook 3370 is no longer within latch notch 3690, a force exerted ontip 3120 may cause tip 3122 separate from handle 3110.

To connect tip 3120 to handle 3110, tip 3120 is pressed onto handle3110. The pressing action causes latch hook 3372 engage latch notch3690, for example, by causing tab 3695 to flex.

As shown in FIG. 42B, when handle 3110 is connected with tip 3120,connection terminals 3160 are mechanically and electrically connectedwith connectors 3250.

FIG. 42C illustrates some minimum clearance distances that may beprovided where the tip 3120 meets the handle 3110 of the electrode 3100.Female connectors 3250 provide electrical power to plug connectionterminals 3160.

For example, minimum clearance distance 4291 to the user is measured byfollowing surfaces and/or air gaps from a connection terminal 3160,between mating surfaces, to a user (as a hand of a user may be placednext to a visible seam between the handle 3110 and tip 3120) as shown.An alternative minimum clearance distance takes a diagonal path from theupper right to the lower left of the air space in Detail J within theconnector, essentially cutting a corner in the currently shown path4291.

In another example, minimum clearance distance 4292 between terminals ismeasured by following mating surfaces and/or air gaps from a connectionterminal 3160 to the other connection terminal 3160 as shown.

Either minimum clearance distance can be equal to or greater than 0.85,1.0, 1.27, 2.5, 3.2, 3.8, 4.4, 5.1, 6.4, 7.6, 10.2, 12.7, or morecentimeters (i.e., 0.33, 0.39, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5,or more inches).

FIGS. 43A and 43B illustrate electrode 3100 in an assembled state withtip 3120 disconnected from handle 3110. As shown, handle 3110 includeshandle base 3210 and handle cap 3240, which house connectors 3250, wires3260, and a portion of cable 3150, such that connectors 3250 areaccessible to connection terminals 3160 through handle cap 3240 when tip3120 is connected with handle 3110. Also as shown, tip 3120 includes tipbase 3510 and tip cap 3520, which house therapeutic terminals 3140,wires 3590, and connection terminals 3160, such that connectionterminals 3160 connect with connectors 3250 when tip 3120 is connectedwith handle 3110.

As shown in FIG. 43A and in other figures, each component (e.g. tip base3510, tip cap 3520, handle base 3210, and handle cap 3240) is mated toone or more adjacent components such that the uninsulated electricalterminals and connectors are housed within a structure, such as a skirtof one component which extends into a skirt hole of the adjacentcomponent. As a result, current leakage between the uninsulatedelectrical terminals and/or connectors is minimized or prevented orsubstantially prevented because the skirts and skirt holes cause thedistance between the uninsulated electrical terminals and/or connectorsalong any path on any surface or combination of surfaces to be equal toor greater than a minimum clearance distance. In some embodiments, theminimum clearance distance is equal to or greater than 0.85, 1.0, 1.27,2.5, 3.2, 3.8, 4.4, 5.1, 6.4, 7.6, 10.2, 12.7, or more centimeters(i.e., 0.33, 0.39, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, or moreinches).

FIG. 43B illustrates examples of the minimum clearance distances inhandle 3100 and in the tip 3120.

For example, minimum clearance distance 4395 to the user is measured byfollowing wiring channel surfaces from a connector 3250, along wire 3260to a user where a hand of the user may be placed next to a visible seambetween handle base 3210 and coaxial cable portion 3150 as shown. Analternative minimum distance follows a diagonal within an air gap withinthe connector, such as a lower left to upper right diagonal near 4394 inSection G-G or upper left to lower right through the air gap in SectionH-H.

Another minimum clearance distance 4394 to the user is measured byfollowing surfaces from a connector 3250, between mating surfaces and/orair gaps, to a user where the hand of the user may be placed next to avisible seam between the handle base 3210 and handle cap 3240 as shown.

Minimum clearance distance 4393 between connectors (conductiveterminals) within handle base 3210 is measured by following matingsurfaces and/or air gaps from a connector 3250 to the other connector3250 as shown.

Yet another minimum clearance distance 4392 between connectors aroundhandle cap 3240 is measured by following the surfaces from a connector3250 out of one recessed connector hole to the other recessed connectorhole to the connector 3250 as shown. Another minimum clearance distanceis an air clearance from a user's hand or finger (when tip 3120 is notattached to handle 3110) at the entrance to the recess down to connector3250.

Minimum clearance distances may be provided also within the tip 3120 ofthe electrode 3100. For example, minimum clearance distance 4397 in tip3120 to the user can be measured from wire 3590 out mating surfacesand/or air gaps between tip base 3510 and tip cap 3520 to a user wherethe hand of the user may be placed next to a visible seam between tipbase 3510 and tip cap 3520 as shown.

Minimum clearance distance 4396 between wires 3590 in tip 3120 ismeasured by following mating surfaces and/or air gaps between tip base3510 and within the tip cap 3520 from wire 3590 to another wire 3590 asshown.

Any of these minimum clearance distances, depending on a particularelectrode or relevant procedure/treatment, can be equal to or greaterthan, for example, 0.85, 1.0, 1.27, 2.5, 3.2, 3.8, 4.4, 5.1, 6.4, 7.6,10.2, 12.7, or more centimeters (i.e., 0.33, 0.39, 0.5, 1, 1.25, 1.5,1.75, 2, 2.5, 3, 4, 5, or more inches).

FIGS. 44A and 44B illustrate an embodiment of an alternative handle3110A. In some embodiments, alternative handle 3110A has featuressimilar or identical to those of handle 3110 and may be used inelectrode 3100 instead of handle 3110, discussed above. Alternativehandle 3110A includes alternative handle base 3210A and alternativehandle cap 3240A. Alternative handle base 3210A has features similar oridentical to those of handle base 3210. Alternative handle cap 3240A hasfeatures similar or identical to those of handle cap 3240.

In some embodiments, cable 3150 is a co-axial cable, having a centralwire surrounded by an insulator and a shielding conductor surroundingthe insulator. An outer insulated sheath also surrounds the shieldingconductor. In such embodiments, splitting wires 3260 from co-axial cable3150 may include removing the outer insulated sheath from an end portionof co-axial cable 3150, thereby exposing the shielding conductor alongthe end portion. In addition, some of the shielding conductor is alsoremoved such that a short portion of the shielding conductor remainsexposed and the insulator surrounding the central wire is exposed alongthe remainder of the end portion. As a result, the modified end portionincludes a relatively long section of insulated central wire extendingfrom a short portion of the exposed shielding conductor. Accordingly, astand-off surface path between the connector 3250 of the insulatedcentral wire and the exposed shielding conductor is provided along theinsulation of the insulated central wire. Accordingly, the relativelylong section of insulated central wire is sized and configured toprovide at least a minimum clearance distance. In some embodiments, theminimum clearance distance is equal to or greater than 0.85, 1.0, 1.27,2.5, 3.2, 3.8, 4.4, 5.1, 6.4, 7.6, 10.2, 12.7, or more centimeters(i.e., 0.33, 0.39, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, or moreinches).

In the illustrated embodiment, the insulated central wire 3260A iscircuitously routed from the exposed shielding conductor 3260B to theconnector 3250 of the insulated central wire. This feature allows forthe desired minimum clearance distance along the surface leakage pathbetween connectors 3250 to be achieved with alternative handle base3210A being shorter than the desired minimum surface leakage pathlength.

In some embodiments, the distance between the shielding conductor 3260Band the hole in handle 3110A by which cable 3150 enters handle 3110A isgreater than a minimum clearance distance. In some embodiments, theminimum clearance distance is equal to or greater than 0.85, 1.0, 1.27,2.5, 3.2, 3.8, 4.4, 5.1, 6.4, 7.6, 10.2, 12.7, or more centimeters(i.e., 0.33, 0.39, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, or moreinches). In some embodiments, a handle may be shorter than the minimumclearance distance, which is accomplished by a circuitous routing of thecable between the hole and shielding conductor 3260B, similar, forexample, to the routing of insulated central wire 3260A illustrated inFIG. 44A.

FIG. 45 illustrates an embodiment of an alternative handle 3110B. Insome embodiments, alternative handle 3110B has features similar oridentical to those of handle 3110 and may be used in electrode 3100instead of handle 3110, discussed above. Alternative handle 3110Bincludes alternative handle base 3210B and alternative handle cap 3240B.Alternative handle base 3210B has features similar or identical to thoseof handle base 3210. Alternative handle cap 3240B has features similaror identical to those of handle cap 3240.

As shown, alternative handle base 3210B and alternative handle cap 3240Bhouse connectors 3250, wires 3260, and a portion of cable 3150, suchthat connectors 3250 are accessible to connection terminals 3160 throughalternative handle cap 3240B when tip 3120 is connected with alternativehandle 3110B.

Alternative handle base 3210B also includes resistor 4510, which isconnected with connectors 3250 by conductors 4520 and is, thereforeelectrically in parallel with a load to which the electrode is attached.Resistor 4510 advantageously ensures that the resistive load experiencedby the pulse generator used with alternative handle 3110B is less than apredetermined maximum. For example, if the maximum desired resistance is200 ohms, resistor 4510 may be 200 ohms. In alternative embodimentsresistor 4510 may be 50 ohms, 75 ohms, 100 ohms, 500 ohms, 1000 ohms, oranother value.

In some embodiments, the value of the resistor may correspond with atype of or an attribute of an electrode. For example, in embodiments ofsome systems, a resistor having a value between 100 ohms and 1000 ohmsmay be electrically adequate. In such systems, a resistor having a valueof about 100 ohms may indicate an electrode of a first type and aresistor having a value of about 200 ohms may indicate an electrode of asecond type. In some embodiments, the value of the resistor may besensed by a controller, and nsPEF pulse parameters to be delivered usingthe electrode may be determined according to the sensed resistor value.In some embodiments, the type or attribute may be related to distancebetween therapeutic terminals, number of therapeutic terminals, type oftherapeutic terminal, or another characteristic.

In some embodiments, a series resistor (not shown) may be placed so asto be electrically in series with the load. The resistor may be, forexample, placed between a wire and a connector or may be spliced into awire such that the electrode is configured to conduct current to or fromthe load through the resistor. In some embodiments, the resistor isplaced elsewhere.

The series resistor guarantees a minimum impedance, and may, forexample, be beneficial in improving a shape of the nsPEF pulsesdelivered by the electrode. In some embodiments, the series resistor maybe about 50 ohms, about 75 ohms, about 100 ohms, about 200 ohms, about500 ohms, about 1000 ohms, or another value.

FIG. 46 is an illustration of a connector 4600. Connector 4600 may, forexample, be used in nsPEF system 100 to connect electrode 102 to housing105. When mated, connector 4600 electrically connects electrode 102 withthe electronic components internal to housing 105, such as an nsPEFpulse generator. Connector 4600 includes features similar to oridentical to those of the other connectors discussed herein, such asconnectors 2700 and 2900 discussed above.

As shown, connector 4600 electrically connects cable 4630 withconnection terminals 4610 through wires 4620. Connector 4600 alsoincludes resistor 4650, which is connected with connection terminals4610 by conductors 4640. Resistor 4650 advantageously ensures that theresistive load experienced by connected the nsPEF pulse generator isless than a predetermined maximum. For example, if the maximum desiredresistance is 200 ohms, resistor 4650 may be 200 ohms. In alternativeembodiments resistor 4650 may be 50 ohms, 75 ohms, 100 ohms, 500 ohms,1000 ohms, or another value.

In some embodiments, resistor 4650 includes circuitry configured tointerface with a controller. For example, the controller may identifythe connector 4600 or an electrode connected to the connector 4600 as aresult of the controller receiving identifying information from thecircuitry. In some embodiments, the circuitry may be configured to countand store the number of nsPEF pulses delivered through the connector4600.

Applying nsPEF to a tumor sufficient to stimulate apoptosis may includeat least the electrical characteristics found experimentally. Forexample, a 100 ns long pulse with a 20 ns rise time to 30 kV/cm(kilovolts per centimeter) at 1 to 7 pulses per second (pps) for 500 to2000 pulses has been found to be sufficient to stimulate apoptosis,depending on the tumor type. Pulsed electric fields of at least 20 kV/cmhave been shown to be effective. A number of pulses greater than 50pulses has also been shown to be effective. Current values between 12 Aand 60 A resulted, depending on the electrode type and skin resistance.

The embodiments of pulse generators described herein have many uses. Forexample, cancer that has metastasized through a subject's bloodstreammay be treated using nsPEF's immune stimulation properties. Fortreatment, circulating tumor cells (CTCs) are isolated from thebloodstream and amassed in vial, test tube, or other suitable in vitroenvironment. In some cases, there may only be a few (e.g., 5, 10), tumorcells that are collected and amassed. Through this mass, an nsPEFelectric field is applied in order to treat the cells. This may causecalreticulin or one or more other damage-associated molecular patterns(DAMPs) to be expressed on the surface membranes of the tumor cells. Thetumor cells may then be introduced back into the subject's bloodstreamby injection, infusion, or otherwise.

In an alternative embodiment, single CTCs may also be isolated from thebloodstream, and each tumor cell treated individually. An automatedsystem that captures CTCs in whole blood using iron nanoparticles coatedwith a polymer layer carrying biotin analogues and conjugated withantibodies for capturing CTCs can automatically capture the tumor cells,and a magnet and or centrifuge can separate them. After separation fromthe antibodies, the CTCs may be treated with nsPEF through a smallcapillary and then reintroduced to the patient's bloodstream.

While examples in the application discuss human and murine subjects, thetreatment of other animals is contemplated. Agricultural animals, suchas horses and cows, or racing animals, such as horses, may be treated.Companion animals, such as cats and dogs, may find special use with thetreatments described herein. It may be difficult for a veterinarian toremove many tumors from a small animal, and cancers may be caughtrelatively late because the animals cannot communicate their advancingpain. Further, the risk inherent in reinjecting tumor cells—albeittreated tumor cells—may be worth the potential benefits of potentiallyhalting a metastasized cancer in a loved pet.

The devices and methods of the present disclosure can be used for thetreatment of any type of cancer, whether characterized as malignant,benign, soft tissue, or solid, and cancers of all stages and gradesincluding pre- and post-metastatic cancers. Examples of different typesof cancer include, but are not limited to, digestive andgastrointestinal cancers such as gastric cancer (e.g., stomach cancer),colorectal cancer, gastrointestinal stromal tumors, gastrointestinalcarcinoid tumors, colon cancer, rectal cancer, anal cancer, bile ductcancer, small intestine cancer, and esophageal cancer; breast cancer;lung cancer; gallbladder cancer; liver cancer; pancreatic cancer;appendix cancer; prostate cancer, ovarian cancer; renal cancer (e.g.,renal cell carcinoma); cancer of the central nervous system; skin cancer(e.g., melanoma); lymphomas; gliomas; choriocarcinomas; head and neckcancers; osteogenic sarcomas; and blood cancers. The devices and methodsof the present disclosure may be also used for the treatment of variousdiseases and abnormalities, including without limitation cardiacdiseases, skin conditions, just to name a few.

Electrical characteristics of nsPEF treatments can be adjusted based ona size and/or a type of a tumor. Types of tumors may include tumors ofdifferent regions of the body, such as the cancerous tumors describedabove.

It is understood that the various embodiments described herein are byway of example only, and are not intended to limit the scope of theinvention. For example, many of the materials and structures describedherein may be substituted with other materials and structures withoutdeviating from the spirit of the invention. Also, various featuresdescribed in reference to certain embodiments may be incorporated andused with other embodiments. The present invention as claimed maytherefore include variations from the particular examples and preferredembodiments described herein, as will be apparent to one of skill in theart. It is understood that various theories as to why the inventionworks are not intended to be limiting.

The above description is illustrative and is not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of the disclosure. The scope of the invention should,therefore, be determined not with reference to the above description,but instead should be determined with reference to the pending claimsalong with their full scope or equivalents.

As noted previously, all measurements, dimensions, and materialsprovided herein within the specification or within the figures are byway of example only.

A recitation of “a,” “an,” or “the” is intended to mean “one or more”unless specifically indicated to the contrary. Reference to a “first”component does not necessarily require that a second component beprovided. Moreover reference to a “first” or a “second” component doesnot limit the referenced component to a particular location unlessexpressly stated.

All publications mentioned herein are incorporated herein by referenceto disclose and describe the methods and/or materials in connection withwhich the publications are cited. The publications discussed herein areprovided solely for their disclosure prior to the filing date of thepresent application. Nothing herein is to be construed as an admissionthat the present invention is not entitled to antedate such publicationby virtue of prior invention. Further, the dates of publication providedmay be different from the actual publication dates, which may need to beindependently confirmed.

1-34. (canceled)
 35. A high voltage therapeutic electrode apparatus, theapparatus comprising: a tip comprising: an insulative tip housing; aplurality of therapeutic terminals supported by the insulative tiphousing; and connection terminals connected with the plurality oftherapeutic terminals; a handle comprising: an insulative handlehousing; electrical connectors adapted to mate with the connectionterminals of the tip, the electrical connectors connected to an inputcable; a sleeved receptacle; and an insulative portion having a wiringchannel within, the insulative portion mating with the sleevedreceptacle; wherein one of the sleeved receptacle and insulative portionis within the tip and the other of the sleeved receptacle and insulativeportion is within the handle, the tip and handle configured to matetogether, and wherein one or both of the insulative portion and thesleeved receptacle is sized and configured to provide a minimumclearance distance between at least one of: 1) the connection terminalsof the tip, or 2) one of the connection terminals and a hand gripportion on the handle, the minimum clearance distance including adistance across internal surfaces of the sleeved receptacle, insulativeportion, or wiring channel.
 36. The apparatus of claim 35, wherein theminimum clearance distance is determined based at least in part on anexpected voltage applied.
 37. The apparatus of claim 35, wherein theminimum clearance distance equals or exceeds 0.85 centimeters.
 38. Theapparatus of claim 35, wherein the apparatus is sized and configured toprovide a second minimum clearance distance between the plurality oftherapeutic terminals and the hand grip portion on the handle.
 39. Theapparatus of claim 38, further comprising an insulative safety structureconfigured to provide the second minimum clearance distance.
 40. Theapparatus of claim 35, further comprising an insulative safety structureconfigured to provide the minimum clearance distance.
 41. The apparatusof claim 40, wherein the insulative safety structure comprises one ormore of the following: a boss, a skirt, a skirt hole, a shield, or afinger stop.
 42. The apparatus of claim 40, wherein the insulativesafety structure is configured to provide the minimum clearance distancewithout increasing a total length of the tip, a total length of thehandle, an actual physical distance between the connection terminals, oran actual physical distance between the connection terminals and afinger stop on the handle.
 43. The apparatus of claim 35, wherein theminimum clearance distance is the shortest distance between twoconductive parts, measured in air or measured along an insulativematerial surface path, that prevents or minimizes an arc.
 44. Theapparatus of claim 35, wherein the apparatus is a sub-microsecond pulsedelectric field electrode apparatus.
 45. The apparatus of claim 35,wherein a length of the therapeutic terminals is adjustable.
 46. Theapparatus of claim 45, wherein the insulative tip housing is movablerelative to the plurality of therapeutic terminals in order to adjust anexposed length of the plurality of therapeutic terminals.
 47. Theapparatus of claim 35, wherein an air clearance distance between theplurality of therapeutic terminals is adjustable.
 48. The apparatus ofclaim 35, wherein the plurality of therapeutic terminals are configuredto rotate.
 49. The apparatus of claim 35, further comprising circuitryconfigured to count and store a number of pulses.
 50. A tip apparatusfor a high voltage nanosecond pulsed electric field (nsPEF) therapeuticelectrode, the apparatus comprising: an insulative tip housing, theinsulative tip housing having: a sleeved receptacle; at least two tipwiring channels sealed from one another within the insulative tiphousing; and at least two insulative portions within the sleevedreceptacle, an inside of each of the at least two insulative portionsforming a portion of one of the at least two tip wiring channels; twohigh voltage input terminals, each high voltage input terminal locatedat one end of one of the at least two insulative portions; and a set oftherapeutic needle electrodes coupled to the two high voltage inputterminals via the at least two tip wiring channels; wherein one or bothof the insulative portion and the sleeved receptacle is sized andconfigured to provide a minimum clearance distance between the two highvoltage input terminals, the minimum clearance distance including adistance across surfaces of the at least two insulative portions or theat least two tip wiring channels.
 51. The apparatus of claim 50, whereinthe minimum clearance distance between the two high voltage inputterminals is determined based at least in part on an expected voltageapplied.
 52. The apparatus of claim 50, further comprising: a handlepermanently or removably connected to the insulative tip housing, thehandle comprising conductive connectors configured to receive the twohigh voltage input terminals.
 53. The apparatus of claim 52, furthercomprising: a tab and a latch notch projecting from the insulative tiphousing, the latch notch configured to resiliently mate with a latchhook of the handle.
 54. The apparatus of claim 50, further comprising: ahand guard surrounding the insulative tip housing at a fixed distancefrom the set of therapeutic needle electrodes.
 55. The apparatus ofclaim 50, further comprising at least one fiducial on the insulative tiphousing radially aligned with a central point of the set of therapeuticneedle electrodes.
 56. A high voltage connector apparatus comprising: anoutlet having electrical terminals; a connector configured to mate withthe outlet, the connector having electrical terminals; and at least twoinsulative portions, wherein the at least two insulative portions are onthe outlet or the connector, and the other of the outlet or theconnector includes holes into which the at least two insulative portionsmate, and wherein one or both of the at least two insulative portions issized and configured to provide a minimum clearance distance between theelectrical terminals of the outlet or between the electrical terminalsof the connector, the minimum clearance distance including a distanceacross surfaces of an insulative portion or a hole.